Advertisement

Pediatric Obesity: Pharmacokinetics and Implications for Drug Dosing

      Abstract

      Purpose

      Clinicians are increasingly likely to have under their care obese children with diseases requiring pharmacotherapy. Optimal drug dosing for this population is unclear. Excess weight likely leads to alterations in pharmacokinetics. The purpose of this article was to describe the pharmacokinetics and pharmacodynamics in overweight and obese children and, where possible, provide recommendations for drug dosing.

      Methods

      EMBASE (1980–May 2015), MEDLINE (1950–May 2015), and International Pharmaceutical Abstracts (1970–May 2015) databases were searched by using the following terms: obesity, morbid obesity, overweight, pharmacokinetics, pharmacodynamics, drug, dose, drug levels, pediatric, and child. The search was limited to English-language articles. References of relevant articles were searched to identify additional studies.

      Findings

      Total body weight (TBW) is an appropriate size descriptor for dosing antineoplastic agents, succinylcholine, and cefazolin. Obese children seem to require less heparin, enoxaparin, and warfarin per kilogram TBW than normal-weight children; providing standard adult doses may be insufficient, however. Obese children may also require less vancomycin and aminoglycosides per kilogram TBW than normal-weight children. For these medications, an alternate size descriptor in children has not been described, and initial dosing based on TBW and monitoring serum concentrations (vancomycin and aminoglycosides) or coagulation parameters (heparin, enoxaparin, and warfarin) is warranted. Obese children require less propofol than normal-weight children; however, there is limited information about the dosing of other anesthetics or opioids.

      Implications

      Limitations to the available data include the inherent design constraints to case reports and retrospective cohort studies, as well as the small numbers of children in some of the studies. Use of normal-weight historical control subjects for obese children in the context of a pharmacokinetic study is not ideal. Although more information is becoming available, our understanding of the pharmacokinetics in obese children is still limited. When dosing information is not available for obese children, it may be necessary to extrapolate from available data in obese adults, but one should consider the effects of the child’s age on pharmacokinetics.

      Key words

      Introduction

      In 2013, the World Health Organization (WHO) estimated that 42 million children aged <5 years were overweight, with 75% of those children living in developing countries.
      WHO [homepage on the internet].
      Worldwide, the prevalence of overweight and obese children increased from 4.2% in 1990 to 6.7% in 2010.
      • de Onis M.
      • Blossner M.
      • Borghi E.
      Global prevalence and trends of overweight and obesity among preschool children.
      In a 2009 to 2010 survey, 12% of children aged 2 to 5 years and 18% of children aged 6 to 19 years in the United States were obese, defined as a body mass index (BMI) ≥95th percentile.
      • Ogden C.L.
      • Carroll M.D.
      • Kit B.K.
      • Flegal K.M.
      Prevalence of obesity and trends in body mass index among US children and adolescents, 1990-2010.
      Compared with normal-weight children, overweight or obese children are at higher risk of chronic diseases, including type 2 diabetes, nonalcoholic fatty liver disease, polycystic ovary syndrome, asthma, obstructive sleep apnea, pseudotumor cerebri, gastroesophageal reflux disease, cholecystitis, and orthopedic problems.
      • Gundogdu Z.
      Relationship between BMI and blood pressure in girls and boys.
      • Weiss R.
      • Kaufman F.R.
      Metabolic complications of childhood obesity.
      • Nathan B.M.
      • Moran A.
      Metabolic complications of obesity in childhood and adolescence: more than just diabetes.
      • Choudhary A.K.
      • Donnelly L.F.
      • Racadio J.M.
      • Strife J.L.
      Diseases associated with childhood obesity.
      • Strauss R.S.
      Childhood obesity.
      An association between childhood obesity and coronary artery disease in adulthood also exists.
      • Balakrisnan P.L.
      Identification of obesity and cardiovascular risk factors in childhood and adolescence.
      Obese children are also more likely to have early-onset puberty.
      • Biro F.M.
      • Khoury P.
      • Morrison J.A.
      Influence of obesity on timing of puberty.
      • Dunger D.B.
      • Ahmed M.L.
      • Ong K.K.
      Effects of obesity on growth and puberty.
      Clinicians are therefore increasingly likely to have under their care obese children with diseases requiring pharmacotherapy. Optimal drug dosing for this population is unclear. Excess body weight likely leads to alterations in pharmacokinetics, and overweight and obese children may be at higher risk of toxicity or reduced therapeutic effectiveness. Although there are a number recent reviews describing drug dosing and pharmacokinetics in obese adults,
      • Janson B.
      • Thursky K.
      Dosing of antibiotics in obesity.
      • Lee J.B.
      • Winstead P.S.
      • Cook A.M.
      Pharmacokinetic alterations in obesity.
      • Casati A.
      • Putza M.
      Anesthesia in the obese patient: pharmacokinetic considerations.
      • Erstad B.L.
      Dosing of medications in morbidly obese patients in the intensive care unit setting.
      • Hall R.G.
      • Jean G.W.
      • Sigler M.
      • Shah S.
      Dosing considerations for obese patients receiving cancer chemotherapeutic agents.
      • Sankaralingam S.
      • Kim R.B.
      • Padwal R.S.
      The impact of obesity on the pharmacology of medications used for cardiovascular risk factor control.
      • Hanley M.J.
      • Abernethy D.R.
      • Greenblatt D.J.
      Effect of obesity on the pharmacokinetics of drugs in humans.
      fewer studies include children.
      • Kendrick J.G.
      • Carr R.R.
      • Ensom M.H.
      Pharmacokinetics and drug dosing in obese children.
      • Mulla H.
      • Johnson T.N.
      Dosing dilemmas in obese children.
      The present article reviews pharmacokinetics and pharmacodynamics in overweight and obese children and provides recommendations for drug dosing.

      Materials and methods

      Search Strategy

      We searched EMBASE (1980–May 2015), MEDLINE (1950–May 2015), and International Pharmaceutical Abstracts (1970–May 2015) databases by using the following search terms: obesity, morbid obesity, overweight, pharmacokinetics, pharmacodynamics, drug, dose, drug levels, pediatric, and child. The search was limited to English-language articles, and the references of relevant articles were also searched to identify additional studies. Studies and case reports that described pharmacokinetics, pharmacodynamics, or drug dosing in obese children were included.

      Definitions

      Definition of “overweight” or “obese” for children is not standardized. Current WHO recommendations, using BMI for age and sex z scores ≥1 SD for overweight (approximately equivalent to the 85th percentile) and ≥2 SDs for obese (approximately equivalent to the 97th percentile) in children aged 5 to 19 years, have been updated from their previous recommendation of using weight-for-length.
      WHO [homepage on the internet].
      • Lobstein T.
      • Baur L.
      • Uauy R.
      International Obesity Task Force. Obesity in children and young people.
      The International Obesity Taskforce and the American Academy of Pediatrics recommend using BMI-for-age and sex ≥85th percentile and 95th percentile to define overweight and obesity, respectively, in children aged >2 years.
      • Lobstein T.
      • Baur L.
      • Uauy R.
      International Obesity Task Force. Obesity in children and young people.
      • Krebs N.F.
      • Himes J.H.
      • Jacobson D.
      • Nicklas T.A.
      • Guilday P.
      • Styne D.
      Assessment of child and adolescent overweight and obesity.
      In children aged ≤2 years, the term obesity is generally not applied.
      • Krebs N.F.
      • Himes J.H.
      • Jacobson D.
      • Nicklas T.A.
      • Guilday P.
      • Styne D.
      Assessment of child and adolescent overweight and obesity.
      In the United States, the Centers for Disease Control and Prevention’s weight, length, and BMI reference charts, which derived data from the National Health and Examination Surveys, are widely used.
      • Lobstein T.
      • Baur L.
      • Uauy R.
      International Obesity Task Force. Obesity in children and young people.
      The WHO revised their growth charts in 2006 based on data from numerous countries in their Multicentre Growth Reference Study.
      • de Onis M.
      • Onyango A.
      • Van den Broeck J.
      • Chumlea W.
      • Martorell R.
      for the WHO Multicentre Growth Reference Study Group
      Measurement and standardization protocols for anthropometric used in the construction of a new international growth reference.
      Many countries, including Canada, recommend using the WHO growth charts. Of note, the accuracy of BMI as an indicator for body “fatness” in children is variable. In children with a BMI ≥95th percentile, it is a good indicator of body “fatness”; however, in children with a lower BMI, differences may more likely be due to differences in fat-free mass.
      • Freedman D.S.
      • Sherry B.L.
      The validity of BMI as an indicator of body fatness and risk among children.

      Body Composition

      Body composition affects disposition of drugs in obese individuals but is difficult to estimate with indirect measures, such as BMI and other size descriptors. Wells et al
      • Wells J.C.
      • Fewtrell M.S.
      • Williams J.E.
      • Haroun D.
      • Lawson M.S.
      • Cole T.J.
      Body composition in normal weight, overweight, and obese children: matched case-control analyses of total and regional tissue masses, and body composition trends in relation to relative weight.
      compared body composition in overweight and obese children with that of age- and sex-matched control subjects. Obese children (n = 38) were on average 3.9 cm taller and had significantly higher total body water, body volume, lean mass, fat mass, and bone mineral content than normal-weight children; these values remained significant after adjusting for age, sex, and height. Information for overweight children was not reported. Fat mass was responsible for 30% to 50% of total weight and 73% of the excess weight in obese children. Lean mass was more hydrated in obese children compared with normal-weight children in this study as well as a report by Battistini et al,
      • Battistini N.
      • Virgili F.
      • Severi S.
      • Brambilla P.
      • Manzoni P.
      • Beccaria L.
      • et al.
      Relative expansion of extracellular water in obese vs. normal children.
      and this finding was attributed to increased extracellular water.

      Dosing Weight

      Methods for dosing medication in children include: age-based dosing, allometric scaling, body surface area (BSA)-based dosing, and weight-based dosing.
      • Bartelink I.H.
      • Rademaker C.M.
      • Schobbem A.F.
      • can den Anker J.N.
      Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations.
      Weight-based dosing is used most commonly in clinical practice, followed by BSA-based dosing used primarily for calculating chemotherapy. BSA is most commonly calculated by using the Mosteller
      • Mosteller R.D.
      Simplified calculation of body-surface area.
      equation: BSA = {[height (cm) × weight (kg)]/3600}1/2.
      Weight and size descriptors used in pharmacokinetic studies include TBW, ideal body weight (IBW), and adjusted body weight (ABW). IBW is derived from Metropolitan Life Insurance Tables or from the Devine or Robinson estimation in adults.
      • Green B.
      • Duffull S.B.
      What is the best size descriptor to use for pharmacokinetic studies in the obese?.
      • Janmahasatian S.
      • Duffull S.B.
      • Ash S.
      • Ward L.C.
      • Byrne N.M.
      • Green B.
      Quantification of lean bodyweight.
      In children, 3 methods have been described for estimating IBW. The McLaren method uses the 50th percentile of weight for height, and the Moore method uses the corresponding weight percentile for height.
      • Phillips S.
      • Eldbeck A.
      • Kirby M.
      • et al.
      Ideal body weight in children.
      The BMI method uses BMI 50th percentile for age × [height (m)]. In adults, an adjusted body weight, using a cofactor of 0.4, is recommended for dosing aminoglycosides: ABW = IBW + 0.4(TBW – IBW).
      • Janson B.
      • Thursky K.
      Dosing of antibiotics in obesity.
      ABW using alternate cofactors has also been described. To our knowledge, ABW has not been validated in children; however, Koshida et al
      • Koshida R.
      • Nakashima E.
      • Taniguchi N.
      • Tsuji A.
      • Benet L.Z.
      • Ichimura F.
      Prediction of the distribution volumes of cefazolin and tobramycin in obese children based on physiological and pharmacokinetic concepts.
      used ABW to estimate tobramycin volume at steady state (Vss).
      Green and Duffull
      • Green B.
      • Duffull S.B.
      What is the best size descriptor to use for pharmacokinetic studies in the obese?.
      reviewed available size descriptors used in adult pharmacokinetic studies: BMI, BSA, IBW, fat-free mass, lean body weight, ABW, TBW, and predicted normal weight. They reviewed 30 drugs, including antineoplastic agents, antibiotics, antiepileptic agents, low-molecular-weight heparins, and opioids. The authors determined that the best size descriptor for calculating Vd was TBW and that the best size descriptor for calculating clearance (CL) was lean body weight. Similar information in children was not available.
      It is important to consider the pharmacokinetics and available dosing information for the given drug when calculating drug doses for obese children. For some drugs, using TBW to calculate weight-based doses could provide a supratherapeutic dose and using IBW could provide a subtherapeutic dose. Regardless of the method used, it is important to consider the recommended adult maximum doses and, in some cases, what is known about dosing in obese adults.
      • Janson B.
      • Thursky K.
      Dosing of antibiotics in obesity.
      • Lee J.B.
      • Winstead P.S.
      • Cook A.M.
      Pharmacokinetic alterations in obesity.
      • Casati A.
      • Putza M.
      Anesthesia in the obese patient: pharmacokinetic considerations.
      • Erstad B.L.
      Dosing of medications in morbidly obese patients in the intensive care unit setting.
      • Hall R.G.
      • Jean G.W.
      • Sigler M.
      • Shah S.
      Dosing considerations for obese patients receiving cancer chemotherapeutic agents.
      • Sankaralingam S.
      • Kim R.B.
      • Padwal R.S.
      The impact of obesity on the pharmacology of medications used for cardiovascular risk factor control.
      • Hanley M.J.
      • Abernethy D.R.
      • Greenblatt D.J.
      Effect of obesity on the pharmacokinetics of drugs in humans.

      Pharmacokinetics and Drug Dosing Differences in Obese Children

      Analgesic Agents

      No studies describing pharmacokinetic parameters of opiate agonists in obese children were found. Commonly used opiate agonists include morphine, hydromorphone, and fentanyl. Codeine is no longer commonly prescribed in children. Opiate agonists are primarily metabolized in the liver and eliminated intact or as metabolites in urine.
      AHFS Drug Information.
      Fentanyl is the most lipophilic of these opiate agonists.
      Burke et al
      • Burke C.N.
      • Voepel-Lewis T.
      • Wagner D.
      • Lau I.
      • Baldock A.
      • Malviya S.
      • Nafia O.
      A retrospective description of anesthetic medication dosing in overweight and obese children.
      performed a retrospective cohort study of 10,498 obese and normal-weight children who received anesthesia for noncardiac surgery (Table I). They recommended dosing for anesthetic medications, including morphine (recommended dosing based on IBW), on the basis of the limited data available for children and on pharmacokinetic data extrapolated from adult information. Obese children compared with normal-weight children were more likely to receive overdoses of morphine. Limitations of this study include that clinical outcomes were not reported and no multivariate analysis or correction for multiple comparisons occurred.
      Table ISummary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of analgesics, anesthetics, and neuromuscular blockers.
      Study and DesignDrug(s)PatientsMethodsResultsConclusions
      Analgesics and anesthetics
       Burke et al,
      • Burke C.N.
      • Voepel-Lewis T.
      • Wagner D.
      • Lau I.
      • Baldock A.
      • Malviya S.
      • Nafia O.
      A retrospective description of anesthetic medication dosing in overweight and obese children.
      retrospective cohort study
      • Midazolam
      • Morphine
      • Succinylcholine
      • Neostigmine
      • Cisatracurium
      • 10,498 obese (BMI >85th %) and normal weight (BMI ≤85th %) children
      • Aged 2–17 y, anesthesia for noncardiac surgery
      • Excluded intubated postoperatively, renal or hepatic disease, neurologic impairment, sleep-disordered breathing
      • Classified medications into dosing groups and recommended doses: midazolam and morphine based on IBW (BMI at 50% for age and sex); succinylcholine and neostigmine based on TBW; and cisatracurium based on LBW calculation used in adults (3.8 × [0.0215 × TBW0.65 × height0.72])
        • Smith H.L.
        • Meldrum D.J.
        • Brennan L.J.
        Childhood obesity: a challenge for the anaesthetist?.
      • Underdose defined as >10% below recommended and overdose defined as >10% above recommended
      • Obese children less likely to receive recommended doses than normal-weight children (OR, 0.69 [95% CI, 0.64–0.75])
      • Obese children more likely than normal-weight children to receive an overdose of morphine (OR, 3.5 [95% CI, 2.7–4.4])
      • Obese children more likely than normal-weight children to receive underdose of succinylcholine (OR, 2 [95% CI, 1.2–3])
      • Obese children are less likely than normal-weight children to receive literature-recommended doses of medications used in anesthesia
       Friedrichsdorf et al,
      • Friedrichsdorf S.J.
      • Postier Nugent A.C.
      • Strobl A.Q.
      Codeine-associated pediatric deaths despite using recommended dosing guidelines: three case reports.
      case report
      • Codeine
      • Case 1: 10-year-old female; weight, 44.5 kg; BMI, 24.4 kg/m2; multiple comorbidities
      • Case 2: 6-year-old female; weight, 44.9 kg; BMI, 26.6 kg/m2; previously healthy, upper respiratory tract infection
      • Case 3: 4-year-old female; weight, 59 kg; BMI, 49.6 kg/m2; multiple comorbidities
      • Case 1: codeine 20–40 mg (0.45–0.9 mg/kg TBW) in afternoon and at bedtime postoperatively; also received diazepam 2 to 4 mg at bedtime
      • Case 2: codeine 10–20 mg (0.22–0.44 mg/kg TBW) at 7 am, 3 pm, and 7 pm in combination with guaifenesin
      • Case 3: codeine 17 mg (0.3 mg/kg TBW) at 8 am, 12 pm, 4 pm, and 8 pm post-tonsillectomy
      • Case 1: found unresponsive at 1:30 am; codeine and morphine concentrations 0.78 and 0.15 mg/L
      • Case 2: appeared blue at 7:45 pm and then unresponsive at 8 am; codeine and morphine concentrations 0.17 and 0.08 mg/L
      • Case 3: found unresponsive in the morning; CYP2D6 analysis showed extensive metabolizer (normal phenotype) of codeine; codeine and morphine concentrations 0.69 and 0.39 mg/L
      • Obese children may be at risk of codeine toxicity
       Olutoye et al,
      • Olutoye O.A.
      • Yu X.
      • Govindan K.
      • Tija I.M.
      • East D.L.
      • Spearman R.
      • Garcia P.J.
      • et al.
      The effect of obesity on the ED95 of propofol for loss of consciousness in children and adolescents.
      prospective observer-blinded observational study
      • Propofol
      • 40 obese (BMI > 95th %) and 40 normal-weight (BMI 25th–84th %) children
      • Aged 3–17 y, previously healthy, propofol anesthesia
      • Propofol dose based on biased coin approach: first child received 1 mg/kg IV. If desired effect not observed, next child received next higher dose in 0.25-mg/kg increments. If desired effect observed, next child randomized 0.95 to 0.05 to receive same dose or next lower dose
      • ED95 = loss of lash reflex at 20 seconds in 95% of patients
      • Median ED95 lower in obese vs normal-weight children (2 mg/kg [95% CI, 1.8–2.2] vs 3.2 mg/kg [95% CI, 2.7–3.2])
      • No significant difference in % of patients with ≥10 mm Hg drop in blood pressure at 2 minutes
      • Obese children require lower propofol doses per kilogram TBW than normal-weight children to achieve the same effect
       Diepstraten et al,
      • Diepstraten J.
      • Chidambaran V.
      • Sadhasivam S.
      • Esslinger H.R.
      • Cox S.L.
      • Inge T.H.
      • Knibbe A.C.
      • et al.
      Propofol clearance in morbidly obese children and adolescents.
      prospective PK study
      • Propofol
      • 20 morbidly obese children (BMI ≥30 kg/m2)
      • Aged 5–18 y, anesthesia with propofol for bariatric surgery
      • Propofol 1000 μg/kg/min, followed by 250–350 μg/kg/min titrated by 25–50 μg/kg/min to target anesthesia depth, and blood pressure and heart rate within 30% of baseline
      • Dose calculated based on ABW = IBW + (0.4 × [TBW – IBW])
      • Blood samples at baseline and 5, 10, 15, 30, 45, and 120 minutes after start of propofol infusion
      • Nonlinear mixed-effects modeling
      • Mean propofol CL, 161 L/h
      • TBW was best size descriptor for CL
      • No covariate or size descriptor predicted Vd
      • Authors suggested propofol dosage should be based on TBW using an allometric function
       Ross et al,
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      literature review and dosing recommendation algorithm
      • 113 commonly prescribed medications in pediatric intensive care units in the United States
      • 122 citations for 66 medications in obese children or adults
      • Decision support tool based on usefulness scoring of literature (score = 1–15), medication PK properties, consequences of overdosing/underdosing, and medication properties (hydrophilic vs lipophilic)
      • 32 medications had no dosing information in obesity
      • 98 medications had no dosing information in obese children
      • Median usefulness score of 7 (range, 0–12.6)
      • Dosing recommendations for medications using ABW (38%), IBW (16%), and TBW (46%)
      Neuromuscular blockers
       Rose et al,

      Rose JB, Theroux MC, Katz MS. The potency of succinylcholine in obese adolescents. Anesth Analg 200;90:576-8.

      RCT
      • Succinylcholine
      • 30 obese (BMI >30 kg/m2) children
      • Aged 9–15 y; succinylcholine for neuromuscular blockade; preoperative midazolam, ranitidine, and metoclopramide; induction with thiopental, fentanyl
      • Reference population: 40 normal-weight children from a previous study
        • Brown T.C.
        • Meretoja O.A.
        • Bell B.
        • Clare D.
        Suxamethonium—electromyographic studies in children.
      • First 20 children were randomized to receive succinylcholine 100 μg/kg or 250 μg/kg TBW and remaining 10 children received succinylcholine 150 μg/kg TBW
      • Neuromuscular blockade monitored with the adductor pollicis muscle response to supramaximal train-of-four stimuli of ulnar nerve every 10 seconds for 30 seconds total
      • Linear regression used to determine effective dose to depress 50%, 90%, and 95% of baseline muscle twitch (ED50, ED90, and ED95)
      • ED50, ED90, and ED95 in μg/kg of TBW were 152.8 (95% CI, 77.8–299.5), 275.4 (95% CI, 142–545.7), and 344.3 (95% CI, 175.3–675.3)
      • Similar to reference population mean (SD) ED50 and ED90: 147 (32) and 270 (70) μg/kg TBW
      • Succinylcholine dose per kilogram TBW provide similar response in obese and normal-weight children
      ABW = adjusted body weight; BMI = body mass index; CL = clearance; CYP = cytochrome P450; ED = effective dose; IBW = ideal body weight; LBW = lean body weight; OR = odds ratio; PK = pharmacokinetic; RCT = randomized controlled trial; TBW = total body weight.
      Friedrichsdorf et al
      • Friedrichsdorf S.J.
      • Postier Nugent A.C.
      • Strobl A.Q.
      Codeine-associated pediatric deaths despite using recommended dosing guidelines: three case reports.
      published a case report of 3 obese children who died after codeine administration at usual or lower than recommended doses (Table I). No anatomic causes of death were found, and accidental overdose was ruled out by examining medication bottles. The authors noted that codeine concentrations were potentially toxic in these patients. No information about obstructive sleep apnea was provided. Obese children should receive codeine cautiously, if at all.
      Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      used a decision support tool to develop dosing recommendations for commonly prescribed medications in critically ill obese children (Table I). Their tool included a usefulness scoring of the pediatric and adult literature, pharmacokinetic parameters of the drug, drug properties (lipophilic vs hydrophilic), and potential consequences of overdosing versus underdosing. They recommended dosing hydromorphone and fentanyl by using ABW (cofactor of 0.25) and morphine by using IBW and titrating to effect, which was based on adult literature.
      Currently, it is unknown what the best size descriptor is for dosing opiate agonists in obese children. Given that these agents have a narrow therapeutic index and that obese children may be more at risk of respiratory adverse events, it seems reasonable to exercise caution with empiric doses and to titrate to effect. Based on extrapolation from adult data, Mortensen et al
      • Mortensen A.
      • Lenz K.
      • Abildstrom H.
      • Lauritsen T.L.
      Anesthetizing the obese child.
      recommend dosing fentanyl based on TBW for induction and lean body weight for maintenance of anesthesia, and Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      recommend dosing based on ABW (cofactor of 0.25) because it is a lipophilic opioid. Both Mortensen et al and Ross et al recommend dosing morphine based on IBW because it is a hydrophilic opioid.

      Anesthetic Agents

      Although we found no pharmacokinetic studies of anesthetic agents in obese children, there are a few studies that describe dosing. There are also a number of review articles that describe the potential morbidity associated with anesthesia in obese children.
      • Mortensen A.
      • Lenz K.
      • Abildstrom H.
      • Lauritsen T.L.
      Anesthetizing the obese child.
      • Veyckemans F.
      Child obesity and anaesthetic morbidity.
      • Samuels P.J.
      Anesthesia for adolescent bariatric surgery.
      • Smith H.L.
      • Meldrum D.J.
      • Brennan L.J.
      Childhood obesity: a challenge for the anaesthetist?.
      In the study by Burke et al
      • Burke C.N.
      • Voepel-Lewis T.
      • Wagner D.
      • Lau I.
      • Baldock A.
      • Malviya S.
      • Nafia O.
      A retrospective description of anesthetic medication dosing in overweight and obese children.
      (Table I), obese children were less likely to receive recommended anesthetic medication doses than normal-weight children (odds ratio [OR], 0.69 [95% CI, 0.64–0.75]). However, when the medications were analyzed separately, there was no difference for midazolam (recommended based on IBW).
      Olutoye et al
      • Olutoye O.A.
      • Yu X.
      • Govindan K.
      • Tija I.M.
      • East D.L.
      • Spearman R.
      • Garcia P.J.
      • et al.
      The effect of obesity on the ED95 of propofol for loss of consciousness in children and adolescents.
      found in their prospective study that obese children required lower propofol doses compared with normal-weight children (Table I). The authors used loss of lash reflex as their marker of effectiveness but noted that the optimal measure of propofol effectiveness has not been determined. Diepstraten et al
      • Diepstraten J.
      • Chidambaran V.
      • Sadhasivam S.
      • Esslinger H.R.
      • Cox S.L.
      • Inge T.H.
      • Knibbe A.C.
      • et al.
      Propofol clearance in morbidly obese children and adolescents.
      performed pharmacokinetic analyses on 20 morbidly obese children and found that TBW was the best size descriptor for CL. Based on this limited information, the authors suggested that the propofol dosage be based on TBW by using an allometric function. From these studies, it is unclear what the best size descriptor is for dosing propofol. TBW may be appropriate for the initial induction dosing of propofol, as recommended by Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      until a better size descriptor becomes available; however, obese children likely require less propofol to maintain the desired level of anesthesia compared with normal-weight children. Additional caution should be exercised when using propofol for procedural sedation in obese children.

      Antibacterial Agents

      Penicillins

      Amoxicillin is a hydrophilic antibiotic that is well absorbed orally, distributes widely, and is eliminated primarily unchanged in urine.
      AHFS Drug Information.
      We found no studies examining the pharmacokinetics of amoxicillin or other penicillins in obese children. Christian-Kopp et al
      • Christian-Kopp S.
      • Sinha M.
      • Rosenberg D.I.
      • Eisendart A.W.
      • McDonald F.W.
      Antibiotic dosing for acute otitis media in children. A weighty issue.
      conducted a retrospective cohort study to examine the dosing of amoxicillin for otitis media (Table II). The authors found that heavier children received lower amoxicillin doses per kilogram TBW, likely due to the prescriber capping the dose at a usual or maximum adult dose; however, the practice of capping the dose at the usual adult maximum did not seem to differ whether prescribing for obese children or for normal-weight children. There was no difference in treatment failure or relapse in the 4 weeks after amoxicillin prescription. Given that the guidelines for otitis media recommend high-dose amoxicillin and that it has a wide margin of safety, prescribing based on TBW in obese children up to a maximum adult dose seems reasonable.
      • Lieberthal A.S.
      • Carroll A.E.
      • Chonmaitree T.
      • et al.
      American Academy of Pediatrics. Clinical Practice Guideline: The diagnosis and management of acute otitis media.
      Table IISummary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of antibacterial and antiviral agents.
      Study and DesignDrug(s)PatientsMethodsResultsConclusions
      Antibacterials
       Christian-Kopp et al,
      • Christian-Kopp S.
      • Sinha M.
      • Rosenberg D.I.
      • Eisendart A.W.
      • McDonald F.W.
      Antibiotic dosing for acute otitis media in children. A weighty issue.
      retrospective cohort study
      • Amoxicillin
      • 359 children
      • Aged 0–18 y (mean, 3.2 y), amoxicillin for otitis media
      • 85 children ≥20 kg; 29 children obese (weight >97th % for age)
      • Compared dosing between obese and normal-weight children ≥20 kg
      • Compared dosing between different weight categories
      • Mean (SD) amoxicillin dose for obese vs normal-weight children ≥20 kg similar (40.8 vs 40.3 mg/kg/d; P = 0.9)
      • Mean (SD) amoxicillin dose higher for children <20 kg vs ≥20 kg: (74.2 [14.7] vs 40.4 [16.6] mg/kg/d; P = 0.0)
      • 8 children exceeded standard adult dose of 1500 mg/d; maximum dose 2400 mg/d
      • Obese children received similar milligram per kilogram TBW doses of amoxicillin
       Koshida et al,
      • Koshida R.
      • Nakashima E.
      • Taniguchi N.
      • Tsuji A.
      • Benet L.Z.
      • Ichimura F.
      Prediction of the distribution volumes of cefazolin and tobramycin in obese children based on physiological and pharmacokinetic concepts.
      prospective PK study
      • Cefazolin
      • Tobramycin
      • 5 obese children
      • Aged 22 mo–9.4 y (mean, 6.8 y), normal kidney and liver function
      • Children 30%–78% above IBW (mean, 63%)
      • Reference population: 6 normal-weight children from previous study
        • Richard A.A.
        • Kim S.
        • Moffett B.S.
        • Bomgaars L.
        • Mahoney D.
        • Yee D.L.
        Comparison of anti-Xa levels in obese and non-obese pediatric patients receiving treatment doses of enoxaparin.
      • Cefazolin 25 mg/kg IV over 30 minutes
      • Tobramycin 2 mg/kg IV over 30 minutes
      • Cefazolin serum concentrations at 30, 50, 70, 90, 110, 130, 160, 190, 220, and 280 minutes after start of infusion
      • Tobramycin serum concentrations at 10, 30, 50, 70, 90, 120, 150, 180, and 240 minutes after start of infusion
      • Noncompartmental analysis; AUC calculated by using the trapezoidal rule
      • No significant difference between obese versus normal-weight reference for cefazolin Vss per kilogram TBW, CL per kilogram TBW, or t½
      • Tobramycin CL per kilogram TBW and t½ similar between obese and normal-weight children
      • Mean (SD) tobramycin Vss per TBW lower for obese vs normal-weight children (0.20 [0.03] vs 0.26 [0.04] L/kg; P< 0.05)
      • Cefazolin pharmacokinetics were not altered in obese children
      • Tobramycin Vd was lower in obese children, but other PK parameters were not altered
       Choi et al,
      • Choi J.J.
      • Moffett B.S.
      • McDade E.J.
      • Palazzi D.L.
      Altered gentamicin serum concentrations in obese pediatric patients.
      retrospective cohort study
      • Gentamicin
      • 25 obese (BMI ≥95th %) and 25 normal-weight (BMI, 5th–85th %) children matched for age, sex, and indication for gentamicin
      • Aged 2–18 y, normal renal function, non-ICU, gentamicin with Cpk and Ctr levels
      • Cpk and Ctr used to calculate PK parameters by using the Sawchuk-Zaske method
      • Cpk extrapolated to end of 30 minutes’ infusion
      • Doses and PK parameters compared between obese and normal-weight children
      • Mean (SD) gentamicin doses given every 8 hours were lower in obese vs normal-weight children (1.86 [0.43] vs 2.25 [0.4] mg/kg; P < 0.01)
      • Mean (SD) Cpk extrapolated higher in obese vs normal-weight children (8.17 [2.02] vs 7.06 [1.52] mg/L; P < 0.05)
      • ke and t½ similar between obese and normal-weight children
      • Mean (SD) Vd per kilogram TBW lower in obese vs normal-weight children (0.20 [0.05] vs 0.28 [0.07] L/kg; P < 0.01)
      • Although CL was not able to be measured, similarity in ke and t½ in context of lower Vd suggest that CL per kilogram TBW may be lower in obese children
       Moffett et al,
      • Moffett B.S.
      • Kim S.
      • Edwards M.S.
      Vancomycin dosing in obese pediatric patients.
      retrospective cohort study
      • Vancomycin
      • 24 obese (BMI ≥95th %) and 24 normal-weight (BMI 25th–75th %) children matched for age and vancomycin dosing schedule (frequency of administration)
      • Aged 2–17 y (mean, 7 y), normal renal function, non-ICU, Ctr drawn appropriately
      • Vancomycin doses and serum concentrations compared between obese and normal-weight children
      • PK parameters calculated for 4 obese children
      • Mean (SD) initial vancomycin dose lower obese vs normal-weight children (14.1 [1.5] vs 14.9 [0.9 mg/kg]; P = 0.03)
      • Mean (SD) Ctr obese vs normal-weight similar (6.9 [4.3] vs 4.8 [3.1] mg/L; P = 0.052)
      • t½, 2.5–3 h
      • Vd, 0.19–0.55 L/kg
      • Obese children had similar Ctr as normal-weight children despite marginally lower empiric doses per kilogram TBW
       Miller et al,
      • Miller M.
      • Miller J.L.
      • Hagemann T.M.
      • Harrison D.
      • Chavez-Bueno S.
      • Johnson P.N.
      Vancomycin dosage in overweight and obese children.
      retrospective cohort study
      • Vancomycin
      • 23 overweight (BMI, 85th–94th %), 35 obese (BMI ≥95th %) and 129 normal-weight (BMI <85th %) children
      • Obese/overweight matched 2.5 to 1 for age and sex
      • Aged 2–17 y; normal renal function, vancomycin Ctr drawn appropriately
      • Vancomycin doses and serum concentrations compared between obese/overweight and normal-weight children
      • Mean (SD) initial vancomycin dose similar between obese/overweight and normal-weight (16.6 [3.9] vs 17.2 [4.1] mg/kg; P = 0.3)
      • Mean (SD) vancomycin Ctr higher in obese/overweight vs normal-weight (9.6 [8.9] vs 7.4 [5.7] mg/L; P = 0.03)
      • No difference in % vancomycin regimens that produced target Ctr between obese/overweight and normal-weight
      • Overweight/obese children receiving similar vancomycin doses per kilogram TBW have higher Ctr vs normal-weight children
       Heble et al,
      • Heble D.E.
      • McPherson C.
      • Nelson M.
      • Hunstad D.A.
      Vancomycin trough concentration in overweight or obese pediatric patients.
      retrospective cohort study
      • Vancomycin
      • 21 overweight (BMI, 85th–94th %), 21 obese (BMI ≥95th %), and 84 normal-weight (BMI, 5th–84th %) children matched by age and dosing regimen
      • Age 2–18 y (mean, 9 y), normal renal function, non-ICU, vancomycin Ctr drawn appropriately
      • Children received empiric weight- and age-based vancomycin doses
      • Vancomycin doses and serum concentrations compared between obese, overweight, and normal-weight children
      • No statistical difference in milligram/kilogram TBW doses between obese, overweight, and normal-weight
      • Median initial Ctr higher in obese/overweight vs normal-weight children (14.4 vs 10.5 mg/L; P < 0.001)
      • No difference in the percentage of patients within target vancomycin Ctr (10–20 mg/L)
      • Obese and overweight children more likely above target (17% vs 2%) and normal-weight children more likely below target (51% vs 19%)
      • Vancomycin doses were not adjusted for overweight or obesity
      • Obese and overweight children had higher Ctr and are more likely to be above target than normal-weight children
      Antiviral agents
       Delgado-Borrego et al,
      • Delgado-Borrego A.
      • Healey D.
      • Negre B.
      • Christofi M.
      • Sabharwal S.
      • Ludwig D.A.
      • Chung R.T.
      • Jonas M.M.
      The influence of body mass index on outcome of pediatric chronic hepatitis C virus infection.
      retrospective cohort study
      • IFN
      • 62 children and young adults
      • Aged 0–20 y (median, 13 y); IFN for hepatitis C
      • Overweight was defined as BMI >85th %
      • IFN 3 million units/m2 (maximum, 5 million units) SC 3 times per week or pegylated IFN alfa 2α 180 µg/1.73 m2 (maximum, 180 µg) SC once weekly, both with or without ribavirin 15 mg/kg/d orally
      • Examined association between BMI and response to therapy (SVR, undetectable HCV at 24 weeks’ posttreatment)
      • Multivariate analysis adjusted for ribavirin use and HCV genotype
      • Univariate analysis: greater percentage of overweight children in the nonresponder group (42%) vs the responder group (19%)
      • Multivariate analysis: higher baseline BMI z scores were associated with lower response to therapy: every 1 SD increase in BMI z score was associated with a 12% reduction in response to therapy
      • Overweight children do not seem to respond as well to IFN
      BMI = body mass index; CL = clearance; Cpk = peak concentration; Ctr = trough concentration; HCV = hepatitis C virus; IBW = ideal body weight; ICU = intensive care unit; IFN = interferon; PK = pharmacokinetic; SVR = sustained virologic response; TBW = total body weight; Vss = volume of distribution at steady-state.
      Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      provide dosing weight recommendations for ampicillin and piperacillin/tazobactam. Their recommendations (ie, to dose both medications according to TBW by using adult maximum doses) are extrapolated from adult studies and take into consideration the wide therapeutic range and the potential for risk of underdosing.

      Cephalosporins

      Cefazolin is a water-soluble antibiotic that is widely distributed and 90% eliminated unchanged in urine.
      AHFS Drug Information.
      Koshida et al
      • Koshida R.
      • Nakashima E.
      • Taniguchi N.
      • Tsuji A.
      • Benet L.Z.
      • Ichimura F.
      Prediction of the distribution volumes of cefazolin and tobramycin in obese children based on physiological and pharmacokinetic concepts.
      found that cefazolin pharmacokinetic parameters in 5 obese children were similar to those of 6 normal-weight children from a previous study
      • Koshida R.
      • Nakashima E.
      • Ichimura F.
      • Nakano O.
      • Watanabe R.
      • Taniguchi N.
      • et al.
      Comparative distribution kinetics of cefazolin and tobramycin in children.
      (Table II). This small study suggests that dosing should be calculated based on TBW (Table III). Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      provide dosing recommendations for critically ill obese children receiving cephalosporins. They suggest dosing cefazolin, cefepime, cefotaxime, ceftazidime, and ceftriaxone by using TBW and adult maximum doses, which are based on risk/benefit assessments.
      Table IIISummary of pharmacokinetic parameters and recommendations for dosing in obese children.
      DrugAUCCL (L/h/kg)Vd (L/kg)Initial Dosing
      Antineoplastic agents
       Busulfan
      • Dupuis L.L.
      • Najdova M.
      • Saunders E.F.
      Retrospective appraisal of busulfan dose adjustment in children.
      • Browning B.
      • Thormann K.
      • Donaldson A.
      • Halverson T.
      • Shinkle M.
      • Kletzel M.
      Busulfan dosing in children with BMIs ≥ 85% undergoing HSCT: a new optimal strategy.
      Not reportedActual BSA
       Cytarabine
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      Not reported↔ (L/h/m2)Not reportedActual BSA
       Daunorubicin
      • Thompson P.
      • Wheeler H.E.
      • Delaney S.M.
      • Lorier R.
      • Broeckel U.
      • et al.
      Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children’s Oncology Group.
      ↔ (L/h/m2)↔ (L/m2)Actual BSA
       Doxorubicin
      • Ritzmo C.
      • Soderhall S.
      • Karlen J.
      • Nygren H.
      • Eksborg S.
      Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient.
      • Thompson P.A.
      • Rosner G.L.
      • Matthay K.K.
      • Moore T.B.
      • Bomgaars L.R.
      • Ellis K.J.
      • et al.
      Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study.
      Not reported↔ (L/h/m2)↔ (L/m2)Actual BSA
       Etoposide
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      • Ritzmo C.
      • Soderhall S.
      • Karlen J.
      • Nygren H.
      • Eksborg S.
      Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient.
      Not reported↔ (L/h/m2)Not reportedActual BSA
       Methotrexate
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      Not reported↔ (L/h/m2)Not reportedActual BSA
       Teniposide
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      Not reported↔ (L/h/m2)Not reportedActual BSA
      Antibiotics
       Aminoglycosides
      • Koshida R.
      • Nakashima E.
      • Taniguchi N.
      • Tsuji A.
      • Benet L.Z.
      • Ichimura F.
      Prediction of the distribution volumes of cefazolin and tobramycin in obese children based on physiological and pharmacokinetic concepts.
      • Choi J.J.
      • Moffett B.S.
      • McDade E.J.
      • Palazzi D.L.
      Altered gentamicin serum concentrations in obese pediatric patients.
      Not reportedTBW or ABW
       Cefazolin
      • Koshida R.
      • Nakashima E.
      • Taniguchi N.
      • Tsuji A.
      • Benet L.Z.
      • Ichimura F.
      Prediction of the distribution volumes of cefazolin and tobramycin in obese children based on physiological and pharmacokinetic concepts.
      Not reportedTBW
       Vancomycin
      • Moffett B.S.
      • Kim S.
      • Edwards M.S.
      Vancomycin dosing in obese pediatric patients.
      • Miller M.
      • Miller J.L.
      • Hagemann T.M.
      • Harrison D.
      • Chavez-Bueno S.
      • Johnson P.N.
      Vancomycin dosage in overweight and obese children.
      • Heble D.E.
      • McPherson C.
      • Nelson M.
      • Hunstad D.A.
      Vancomycin trough concentration in overweight or obese pediatric patients.
      Not reportedNot reportedTBW
      ↔ = no relative difference, compared with normal-weight; ↓ = relatively lower compared with normal-weight; ABW = adjusted body weight; BSA = body surface area; CL = clearance; TBW = total body weight.

      Aminoglycosides

      Aminoglycoside antibiotics are water soluble, distribute primarily into extracellular fluid, and are eliminated mainly by glomerular filtration.
      AHFS Drug Information.
      Koshida et al
      • Koshida R.
      • Nakashima E.
      • Taniguchi N.
      • Tsuji A.
      • Benet L.Z.
      • Ichimura F.
      Prediction of the distribution volumes of cefazolin and tobramycin in obese children based on physiological and pharmacokinetic concepts.
      found that tobramycin CL and t½ were similar in 5 obese children compared with 6 normal-weight children from a previous study
      • Koshida R.
      • Nakashima E.
      • Ichimura F.
      • Nakano O.
      • Watanabe R.
      • Taniguchi N.
      • et al.
      Comparative distribution kinetics of cefazolin and tobramycin in children.
      ; however, Vss per TBW was significantly lower for the obese children (Table II). The authors developed an equation to predict Vss of tobramycin in obese children: Vss = 0.261 × {IBW (kg) + 0.4 × [TBW (kg) – IBW (kg)]}. Comparing their equation with calculated pharmacokinetic parameters in the obese children, the difference was 6.8%.
      Choi et al
      • Choi J.J.
      • Moffett B.S.
      • McDade E.J.
      • Palazzi D.L.
      Altered gentamicin serum concentrations in obese pediatric patients.
      compared gentamicin levels and pharmacokinetic parameters in 25 obese children and 25 normal-weight children (Table II). The calculated ke and t½ were similar between obese and normal-weight children; however, Vd was lower in obese children. Although the authors were not able to measure CL, the similarity in ke and t½ suggests that CL per kilogram TBW may be lower in obese children. There were no differences in nephrotoxicity, duration of hospital stay, or gentamicin therapy between groups.
      Based on these studies, it is unclear if gentamicin and tobramycin’s CL per TBW in obese children is similar to or lower than normal-weight children. This suggests that the total daily dose per kilogram TBW could be based on TBW or on ABW = IBW + 0.4(TBW – IBW), similar to adults.
      • Janson B.
      • Thursky K.
      Dosing of antibiotics in obesity.
      Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      suggest using ABW to dose gentamicin and tobramycin in critically ill obese children. Given that aminoglycoside concentrations are typically measured in practice, empiric dosing based on TBW or ABW would be appropriate, taking into account patient-specific factors such as renal function, illness severity, and extent of obesity (Table III).

      Vancomycin

      Vancomycin distributes widely into body tissues and fluid and is eliminated primarily by glomerular filtration. In children, the Vd for vancomycin is 0.26 to 1.05 L/kg, and t½ varies from 6 to 10 hours in neonates and 2 to 4 hours in infants and children.
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric & Neonatal Dosage Handbook.
      Three retrospective studies have examined vancomycin dosing and serum trough concentrations in overweight and/or obese children compared with normal-weight children.
      Moffett et al
      • Moffett B.S.
      • Kim S.
      • Edwards M.S.
      Vancomycin dosing in obese pediatric patients.
      compared empiric vancomycin doses and serum trough concentrations (Ctr) in 24 obese and 24 normal-weight children (Table II). Most children received vancomycin at 8-hour intervals. Despite receiving lower empiric doses (difference, 0.8 mg/kg), obese children had similar Ctr levels. In the 4 obese children who had vancomycin peak and trough concentrations, Vd and t½ were similar to published values in children.
      Miller et al
      • Miller M.
      • Miller J.L.
      • Hagemann T.M.
      • Harrison D.
      • Chavez-Bueno S.
      • Johnson P.N.
      Vancomycin dosage in overweight and obese children.
      compared vancomycin doses and Ctr in 23 overweight, 35 obese, and 129 normal-weight children (Table II). Overweight/obese children received similar vancomycin doses but had higher Ctr levels compared with normal-weight children. There was no difference between overweight/obese children and normal-weight children in the percentage of concentrations within target. There was no difference in occurrence of nephrotoxicity or red man syndrome between groups.
      Heble et al
      • Miller M.
      • Miller J.L.
      • Hagemann T.M.
      • Harrison D.
      • Chavez-Bueno S.
      • Johnson P.N.
      Vancomycin dosage in overweight and obese children.
      compared 21 overweight children and 21 obese children versus 84 normal-weight children who were receiving vancomycin (Table II). There was no statistical difference in milligram per kilogram TBW doses between obese, overweight, and normal-weight children, suggesting that there was no dose adjustment for obesity. Median initial trough levels were higher in the obese/overweight children compared with the normal-weight children. Although there was no difference in the percentage of patients within target vancomycin trough (10–20 mg/L) between obese, overweight, and normal-weight children, obese and overweight children were more likely to be above target, and normal-weight children were more likely to be below target.
      Based on the aforementioned studies, it seems that obese and overweight children achieve higher vancomycin trough concentrations at similar milligram per kilogram TBW doses than their normal-weight counterparts, but that there is no difference in the percentage of patients who are within target range. Given that vancomycin serum concentrations are typically monitored in clinical practice, dosing obese and overweight children based on TBW seems reasonable until a better size descriptor is available (Table III).

      Anticoagulant Agents

      Heparin

      Heparin is highly bound to plasma proteins, and its Vd approximates that of blood volume.
      AHFS Drug Information.
      It is cleared primarily via the reticuloendothelial system and endothelial cells and minimally by the liver and kidneys. Two retrospective studies examined the impact of obesity on heparin dosing in children.
      Moffett et al
      • Moffett B.S.
      • Terula J.
      • Petit C.
      Heparin dosing in obese pediatric patients in the cardiac catheterization laboratory.
      studied 39 obese children and 39 normal-weight children who received an intravenous heparin bolus for cardiac catheterization (Table IV). There was no difference in heparin bolus dose per kilogram TBW, activated clotting time (ACT), or need for additional heparin boluses between the obese and normal-weight children. The authors noted that results were not what they expected and that ACT may not be the optimal marker of heparin response.
      Table IVSummary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of anticoagulant agents.
      Study and DesignDrug(s)PatientsMethodsResultsConclusions
      Moffett et al,
      • Moffett B.S.
      • Terula J.
      • Petit C.
      Heparin dosing in obese pediatric patients in the cardiac catheterization laboratory.
      retrospective cohort study
      • Heparin
      • 39 obese (BMI ≥95th %) and 39 normal-weight (BMI <95th %) children matched by age, sex, and catheterization procedure
      • Aged 2–18 y (mean, 10 y), heparin bolus for cardiac catheterization, ≥1 ACT within 120 minutes of heparin bolus
      • Compared heparin dose and ACT between obese and normal-weight children
      • Mean (SD) heparin dose for obese vs normal-weight children was similar (63.6 [23.6] vs 72.3 [24.9] U/kg; P = 0.12)
      • No difference in % change in ACT from baseline between obese and normal-weight children (196 [106] and 165 [97] %; P = 0.17)
      • No difference in need for >1 heparin bolus between obese and normal-weight children (6 and 8; P = 0.4)
      • Obese children receive similar doses and have similar ACT responses compared with normal-weight children
      Taylor et al,
      • Taylor B.N.
      • Bork S.J.
      • Kim S.
      • Moffett B.S.
      • Lee D.L.
      Evaluation of weight-based dosing of unfractionated heparin in obese children.
      retrospective cohort study
      • Heparin
      • 25 obese (BMI ≥95th %) and 25 normal-weight (BMI, 25th–75th %) children
      • Aged 2–18 y (mean, 12 y), continuous heparin infusion, ≥1 aPTT or anti-Xa at least 4 hours after start of heparin infusion
      • Compared heparin dose and aPTT or anti-Xa between obese and normal-weight children
      • Mean (SD) initial heparin dose lower in obese vs normal-weight (17.4 [4.2] vs 20.2 [3.3] U/kg/h; P = 0.013)
      • Mean (SD) maintenance heparin dose lower in obese vs normal-weight (19.1 [6.7] vs 24.3 [9.6] U/kg/h; P = 0.033)
      • Mean (SD) initial anti-Xa activity higher in obese vs normal-weight (0.45 [0.32] vs 0.29 [0.19] U/mL; P = 0.045)
      • Mean (SD) time to achieve 2 therapeutic anti-Xa concentrations (0.35–0.7 U/L) shorter in obese vs normal-weight (27.3 [17.7] vs 44 [31.7] hours; P = 0.045)
      • Mean time to achieve therapeutic aPTT was not different
      • No difference in % of patients with treatment interruption for supratherapeutic aPTT or anti-Xa concentration or bleeding
      • Obese children require lower heparin infusion dose per kilogram TBW to achieve target aPTT or anti-Xa concentrations
      Lewis et al,
      • Lewis T.V.
      • Johnson P.N.
      • Nebbia A.M.
      • Dunlap M.
      Increased enoxaparin dosing is required for obese children.
      case report
      • Enoxaparin
      • Case 1: 16-year-old male; BMI, 105.9 kg/m2
      • Case 2: 16-year-old male; BMI, 95.7 kg/m2
      • Case 3: 11-year-old male; BMI, 29.9 kg/m2
      • Enoxaparin prophylaxis during hospitalization
      • All children initiated on usual adult enoxaparin prophylactic dose 40 mg SC daily but required dosage increases to achieve target anti-Xa concentrations (0.1–0.3 U/L)
      • Case 1: 90–100 mg SC every 12 hours (0.28–0.33 mg/kg/dose)
      • Case 2: 45 mg SC every 12 hours (0.15 mg/kg/dose)
      • Case 3: 40 mg SC every 12 hours (0.49 mg/kg/dose)
      • Enoxaparin dose required to achieve target anti-Xa concentrations for prophylaxis lower than the recommended empiric pediatric dose but higher than adult doses in 2 of the 3 patients
      Richard et al,
      • Richard A.A.
      • Kim S.
      • Moffett B.S.
      • Bomgaars L.
      • Mahoney D.
      • Yee D.L.
      Comparison of anti-Xa levels in obese and non-obese pediatric patients receiving treatment doses of enoxaparin.
      retrospective cohort study
      • Enoxaparin
      • 30 obese (BMI ≥95th %) and 30 normal-weight (BMI, 25th–75th %) children matched based on age, sex, and acuity of care
      • Aged 2–18 y (mean, 11 y), enoxaparin treatment doses (1 mg/kg SC every 12 hours to target anti-Xa 0.5–1 U/L), anti-Xa measurement 4 to 6 hours after the second dose
      • Compared enoxaparin dosing and anti-Xa levels between obese and normal-weight children
      • Initial enoxaparin dosing no different in obese vs normal-weight children
      • Mean (SD) first anti-Xa concentration was higher in obese vs normal-weight children (0.67 [0.27] vs 0.53 [0.24] U/L; P = 0.028)
      • Mean (SD) therapeutic dose lower was in obese vs normal-weight children (0.81 [0.2] vs 1.1 [0.4] mg/kg; P = 0.005)
      • No statistical difference in % of obese vs normal-weight children with supratherapeutic anti-Xa during treatment (70% vs 47%; P = 0.12)
      • Obese children require lower enoxaparin dose per kilogram TBW to achieve therapeutic anti-Xa concentrations
      Moffett et al,
      • Moffett B.C.
      • Bomgaars L.R.
      Response to warfarin therapy in obese pediatric patients dosed according to institutional guidelines.
      retrospective cohort study
      • Warfarin
      • 10 obese (BMI ≥95th %) and 20 normal-weight (BMI, <95th %) children matched based on age and sex
      • Aged 2–18 y (mean, 14 y), warfarin
      • Excluded Fontan procedure or mechanical circulatory support
      • Empiric warfarin dose 0.2 mg/kg/d (maximum, 5 mg) or 0.1 mg/kg/d (maximum, 2.5 mg) if drug interaction
      • Doses were adjusted according to the hospital’s algorithm
      • Compared obese vs normal-weight children warfarin doses and INR
      • Lower mean (SD) empiric and adjusted warfarin doses for obese vs normal-weight children (0.06 [0.02] vs 0.11 [0.04], P < 0.01, and 0.09 [0.04] vs 0.13 [0.05] mg/kg/d, P = 0.04)
      • Median time (range) to therapeutic INR was longer in obese vs normal-weight children (6 [4–28] vs 3 [1–10] days; P < 0.01)
      • No statistical difference in % of obese vs normal-weight children with supratherapeutic INR during treatment (10% vs 40%; P = 0.09
      • Obese children require lower warfarin doses per kilogram TBW, but empiric doses that are capped at 5 or 2.5 mg may prolong time to therapeutic INR
      ACT = activated clotting time; aPTT = activated partial thromboplastin time; BMI = body mass index; INR = international normalized ratio; TBW = total body weight.
      Taylor et al
      • Taylor B.N.
      • Bork S.J.
      • Kim S.
      • Moffett B.S.
      • Lee D.L.
      Evaluation of weight-based dosing of unfractionated heparin in obese children.
      evaluated 25 obese and 25 normal-weight children who received heparin intravenous infusions (Table IV). Obese children received lower initial and maintenance doses of heparin and had higher initial anti-Xa levels than normal-weight children. However, obese children achieved therapeutic anti-Xa levels faster than normal-weight children. There was no difference in time to therapeutic activated partial thromboplastin time (aPTT) or in treatment interruptions. Only 1 bleeding event occurred in a normal-weight child. A limitation of this study was that the authors did not describe the timing of the anti-Xa or aPTT levels. The authors noted that differences between anti-Xa concentration and aPTT suggest a lack of agreement in assays.
      Limitations to both studies included small sample size and inability to perform multivariate analysis or correct for multiple comparisons. The ability to interpret these studies may be limited by the different assays used. It does seem, however, that obese children should receive a heparin bolus dose based on TBW but that they may require lower heparin infusion doses (Table V). Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      suggest dosing heparin infusions by using ABW (cofactor of 0.4) in critically ill obese children based on the hydrophilic nature of heparin and the water content of adipose tissue.
      Table VSummary of pharmacodynamic parameters and recommendations for dosing in obese children.
      DrugPharmacodynamic ParameterInitial Dosing
      Anticoagulant agents
       Heparin
      • Moffett B.S.
      • Terula J.
      • Petit C.
      Heparin dosing in obese pediatric patients in the cardiac catheterization laboratory.
      • Taylor B.N.
      • Bork S.J.
      • Kim S.
      • Moffett B.S.
      • Lee D.L.
      Evaluation of weight-based dosing of unfractionated heparin in obese children.
      Anti-Xa ↑TBW
      aPTT
      ACT ↔
       Enoxaparin
      • Lewis T.V.
      • Johnson P.N.
      • Nebbia A.M.
      • Dunlap M.
      Increased enoxaparin dosing is required for obese children.
      • Richard A.A.
      • Kim S.
      • Moffett B.S.
      • Bomgaars L.
      • Mahoney D.
      • Yee D.L.
      Comparison of anti-Xa levels in obese and non-obese pediatric patients receiving treatment doses of enoxaparin.
      Anti-Xa ↑TBW; recommend against empiric adult dose for prophylaxis
       Warfarin
      • Moffett B.C.
      • Bomgaars L.R.
      Response to warfarin therapy in obese pediatric patients dosed according to institutional guidelines.
      ↑ time to therapeutic INRTBW; recommend against capping initial dose at 5 mg (or 2.5 mg if drug interaction)
      Antiviral agent
       Interferon
      • Delgado-Borrego A.
      • Healey D.
      • Negre B.
      • Christofi M.
      • Sabharwal S.
      • Ludwig D.A.
      • Chung R.T.
      • Jonas M.M.
      The influence of body mass index on outcome of pediatric chronic hepatitis C virus infection.
      ↓SVRTBW; optimal dose unclear
      Antihypertensive agents
       ACE inhibitor or ARB
      • Hanafy S.
      • Pinsk M.
      • Jamali F.
      Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease.
      • Meyers K.E.
      • Lieberman K.
      • Solar-Yohay S.
      • Han G.
      • Shi V.
      The efficacy and safety of valsartan in obese and non-obese pediatric hypertensive patients.
      BP response ↔Empiric low dose
       CCB
      • Hanafy S.
      • Pinsk M.
      • Jamali F.
      Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease.
      BP response ↓Empiric dose; may need to be increased; combination BP lowering therapy may be required
      Neuromuscular blocking agent
       Succinylcholine

      Rose JB, Theroux MC, Katz MS. The potency of succinylcholine in obese adolescents. Anesth Analg 200;90:576-8.

      Baseline muscle twitch ↔TBW
      Vitamins
       Vitamin D
      • Rajakumar K.
      • Fernstrom J.D.
      • Holick M.F.
      • Janosky J.E.
      • Greenspan S.L.
      Vitamin D status and response to vitamin D3 in obese vs. non-obese African American children.
      • Mark S.
      • Lambert M.
      • Delvin E.E.
      • O’Loughlin J.
      • Tremblay A.
      • Gray-Donald K.
      Higher vitamin D intake is needed to achieve serum 25(OH)D levels greater than 50 nmol/L in Quebec youth at high risk of obesity.
      • Aguirre Castaneda R.
      • Nader N.
      • Weaver A.
      • Singh R.
      • Kumar S.
      Response to vitamin D3 supplementation in obese and non-obese Caucasian adolescents.
      ↔ or ↓ 1,25(OH)2D and 25 (OH) DEmpiric dose
      ↔ = no relative difference, compared with normal-weight; ↓ = relatively lower compared with normal-weight; ↑ = relatively higher compared with normal-weight; 1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; ACE = angiotensin-converting enzyme; ACT = activated clotting time; aPTT = activated partial thromboplastin time; ARB = angiotensin receptor blocker; BP = blood pressure; CCB = calcium channel blocker; INR = international normalized ratio; SVR = sustained virologic response; TBW = total body weight.

      Enoxaparin

      Enoxaparin is the low-molecular-weight heparin that is most commonly used in children. It is primarily eliminated by the kidneys.
      AHFS Drug Information.
      Lewis et al
      • Lewis T.V.
      • Johnson P.N.
      • Nebbia A.M.
      • Dunlap M.
      Increased enoxaparin dosing is required for obese children.
      reported on 3 hospitalized children who received prophylactic enoxaparin (Table IV). All children were initiated on usual adult enoxaparin prophylactic doses but required dosage increases to achieve target anti-Xa concentrations. Adjusted doses were lower than the recommended empiric pediatric dose of 0.5 mg/kg TBW SC every 12 hours in 2 of the 3 patients.
      • Taketomo C.K.
      • Hodding J.H.
      • Kraus D.M.
      Pediatric & Neonatal Dosage Handbook.
      Richard et al
      • Richard A.A.
      • Kim S.
      • Moffett B.S.
      • Bomgaars L.
      • Mahoney D.
      • Yee D.L.
      Comparison of anti-Xa levels in obese and non-obese pediatric patients receiving treatment doses of enoxaparin.
      studied 30 obese children and 30 normal-weight children who received enoxaparin treatment doses (Table IV). Both groups received similar initial enoxaparin doses per kilogram TBW; however, obese children had higher initial anti-Xa concentrations and required lower maintenance enoxaparin doses than normal-weight children. Both groups of children required lower doses of enoxaparin over time. The authors noted that they could not control for other factors (eg, puberty) which may affect enoxaparin dosing.
      From the case report and the retrospective study,
      • Lewis T.V.
      • Johnson P.N.
      • Nebbia A.M.
      • Dunlap M.
      Increased enoxaparin dosing is required for obese children.
      • Richard A.A.
      • Kim S.
      • Moffett B.S.
      • Bomgaars L.
      • Mahoney D.
      • Yee D.L.
      Comparison of anti-Xa levels in obese and non-obese pediatric patients receiving treatment doses of enoxaparin.
      it seems that obese children may require lower doses of enoxaparin per kilogram TBW than normal-weight children for treatment or prophylaxis to achieve target anti-Xa concentrations; however, standard empiric adult doses may not be appropriate. Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      suggest dosing enoxaparin using ABW (cofactor of 0.4) in critically ill obese children and titrating to effect. For enoxaparin treatment, standard pediatric empiric dosing based on TBW and monitoring anti-Xa concentrations can also be used.

      Warfarin

      Moffett et al
      • Moffett B.C.
      • Bomgaars L.R.
      Response to warfarin therapy in obese pediatric patients dosed according to institutional guidelines.
      conducted a retrospective cohort study of 10 obese and 20 normal-weight children who received warfarin (Table IV). Obese children had lower empiric and adjusted warfarin doses than normal-weight children. Time to therapeutic international normalized ratio (INR) was longer in obese versus normal-weight children. There was no difference in the percentage of patients with supratherapeutic INR. Data regarding bleeding episodes and outpatient therapy were not captured. The authors noted that the small sample size precluded multivariate analysis to account for other factors affecting warfarin dose (eg, genetics, diet, drug interactions). This study suggests that although obese children may require lower doses per kilogram TBW than normal-weight children, capping initial doses at 5 mg (or 2.5 mg in case of drug interaction) may unnecessarily prolong the time to achieve a therapeutic INR.

      Antineoplastic Agents

      Doses of chemotherapy are commonly calculated based on a patient’s BSA, using TBW. In 2012, the American Society of Clinical Oncology published guidelines suggesting that obese adults receive curative chemotherapy based on TBW; this recommendation was based primarily on evidence that alternate size descriptors could result in underdosing and lead to less effective therapy and that dosing based on TBW was not routinely associated with excess toxicity.
      • Sparreboon A.
      • Wolff A.C.
      • Mathijssen R.H.
      • Chatelut E.
      • Rowinsky E.K.
      • Verweij J.
      • et al.
      Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese.
      • Hunter R.J.
      • Navo M.A.
      • Thaker P.H.
      • Bodurka D.C.
      • Wolf J.K.
      • Smith J.A.
      Dosing chemotherapy in obese patients: actual versus assigned body surface area (BSA).
      • Griggs J.J.
      • Mangu P.B.
      • Anderson H.
      • et al.
      Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline.
      We found no similar guidelines for obese children. A retrospective cohort study by Baillargeon et al
      • Baillargeon J.
      • Langevin A.M.
      • Lewis M.
      • Thomas P.J.
      • Mullins J.
      • Dugan J.
      • et al.
      L-asparaginase as a marker of chemotherapy dose modification in children with acute lymphoblastic leukemia.
      comparing chemotherapy dose calculations between obese and normal-weight children with leukemia found that 7% of obese children received less than the protocol-specified dose. Although this study did not report clinical outcomes, there are multiple cohort studies describing efficacy and safety outcomes in obese versus normal-weight children receiving treatment for acute myeloid leukemia or acute lymphocytic leukemia (ALL) (Table VI).
      • Inaba H.
      • Surprise H.C.
      • Pounds S.
      • Cao X.
      • Howard S.C.
      • Ringwald-Smith K.
      • Buaboonnam J.
      • Dahl G.
      • et al.
      Effect of body mass index on the outcome of children with acute myeloid leukemia.
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      • Gelelete C.B.
      • Pereira S.H.
      • Azevedo A.M.
      • Thiago L.S.
      • Mundim M.
      • Land M.G.
      • Costa E.S.
      Overweight as a prognostic factor in children with acute lymphoblastic leukemia.
      • Butturini A.M.
      • Dorey F.J.
      • Lange B.J.
      • Henry D.W.
      • Gaynon P.S.
      • Fu C.
      • Franklin J.
      • Siegel S.E.
      • et al.
      Obesity and outcome in pediatric acute lymphoblastic leukemia.
      • Lange B.J.
      • Gerbing R.B.
      • Feusner J.
      • Skilnik J.
      • Sacks N.
      • Smith F.O.
      • Alonza T.A.
      Mortality in overweight and underweight children with acute myeloid leukemia.
      Table VISummary of studies describing the effect of obesity on cancer outcomes.
      Study and DesignPatientsChemotherapy and MethodsEfficacySafety
      ALL
       Hijiya et al,
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      retrospective cohort study
      • 621 children age >1 y who received treatment for ALL
      • Chemotherapy doses based on BSA calculated by using TBW
      • Efficacy analysis, but not safety analysis, was adjusted for potential confounders of age, sex, WBC at diagnosis, immunophenotype, and DNA index
      • No significant association between BMI and complete remission, OS, cumulative incidence of relapse
      • No significant association between BMI and grade 3 or 4 toxicity
       Galelete et al,
      • Gelelete C.B.
      • Pereira S.H.
      • Azevedo A.M.
      • Thiago L.S.
      • Mundim M.
      • Land M.G.
      • Costa E.S.
      Overweight as a prognostic factor in children with acute lymphoblastic leukemia.
      retrospective cohort study
      • 181 children, 93% <10 y, 36% overweight or obese (BMI 1 or 2 SDs above z score for age), treatment for ALL
      • Chemotherapy doses based on BSA calculated by using TBW
      • Multivariate analysis adjusted for age, WBC count, and response after first week of treatment
      • Five-year EFS lower in overweight/obese children vs normal-weight children (61% vs 81%; P = 0.03)
      • Obesity independently associated with lower 5-year EFS (HR, 1.92 [95% CI, 1.42–2.6])
      • Not reported
       Butturini et al,
      • Butturini A.M.
      • Dorey F.J.
      • Lange B.J.
      • Henry D.W.
      • Gaynon P.S.
      • Fu C.
      • Franklin J.
      • Siegel S.E.
      • et al.
      Obesity and outcome in pediatric acute lymphoblastic leukemia.
      retrospective cohort study
      • 343 obese (BMI ≥95th %) and 3917 normal-weight children, aged 0–20 y, treatment for ALL
      • Excluded Down syndrome or central nervous system disease
      • Chemotherapy doses were based on BSA using TBW in 98.5% of obese children, except vincristine, which had a maximum dose of 2 mg
      • Multivariate analysis adjusted for age, WBC count, race, and bone marrow response at day 7
      • Toxicity not uniformly reported
      • Obesity associated with lower 5-year EFS (HR, 1.36 [95% CI, 1.04–1.77])
      • Obesity associated with more relapses (HR, 1.29 [95% CI, 1.02–1.56])
      • Obesity had no effect on length of interval between diagnosis and completion of fourth phase, hospitalization, death during induction, or death secondary to toxicity
      AML
       Inaba et al,
      • Inaba H.
      • Surprise H.C.
      • Pounds S.
      • Cao X.
      • Howard S.C.
      • Ringwald-Smith K.
      • Buaboonnam J.
      • Dahl G.
      • et al.
      Effect of body mass index on the outcome of children with acute myeloid leukemia.
      retrospective cohort study
      • Children and young adults aged 2–20 years who received treatment for AML
      • Overweight, obese, and normal-weight defined as BMI 85 to <95th %, ≥95th %, and 5 to <85th %
      • Chemotherapy doses not modified on the basis of BMI
      • Multivariate regression with age, leukocyte count, French-American-British classification as predictors and stratified according to study protocol
      • Overweight/obese children had lower 5-year OS vs normal-weight children (HR, 1.84 [95% CI, 1.22–2.78])
      • No statistical difference in EFS (HR, 1.4 [0.96–2.04])
      • Overweight/obese children had more grade 2 or 3 infections
      • Treatment-related mortality higher in overweight/obese children compared with normal-weight children
       Lange et al,
      • Lange B.J.
      • Gerbing R.B.
      • Feusner J.
      • Skilnik J.
      • Sacks N.
      • Smith F.O.
      • Alonza T.A.
      Mortality in overweight and underweight children with acute myeloid leukemia.
      retrospective cohort study
      • 768 children and young adults, aged 0–20 years; treatment for AML
      • Excluded Down syndrome
      • Overweight and normal-weight defined as BMI ≥95th % and 11th–94th % (for children aged >2 y) or weight-for-length ≥95th % and 11th–94th % (for children aged 1–2 y)
      • Chemotherapy was dosed based on TBW or BSA calculated by using TBW
      • Multivariate analysis adjusted for age, race, WBC count, cytogenetics, and allogeneic bone marrow transplant
      • Overweight children had lower OS than normal-weight children (HR, 1.88 [95% CI, 1.25–2.83])
      • Treatment-related mortality higher in overweight children (HR, 3.49 [95% CI, 1.99–6.1])
      • Overweight children more likely to die before first remission, with most common cause being infection
      ALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; BMI = body mass index; BSA = body surface area; EFS = event-free survival; HR = hazard ratio; OS = overall survival; TBW = total body weight; WBC = white blood cell count.
      It seems that obesity may be associated with lower survival in children with leukemia, despite their receiving chemotherapy doses based on TBW.
      • Inaba H.
      • Surprise H.C.
      • Pounds S.
      • Cao X.
      • Howard S.C.
      • Ringwald-Smith K.
      • Buaboonnam J.
      • Dahl G.
      • et al.
      Effect of body mass index on the outcome of children with acute myeloid leukemia.
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      • Gelelete C.B.
      • Pereira S.H.
      • Azevedo A.M.
      • Thiago L.S.
      • Mundim M.
      • Land M.G.
      • Costa E.S.
      Overweight as a prognostic factor in children with acute lymphoblastic leukemia.
      • Butturini A.M.
      • Dorey F.J.
      • Lange B.J.
      • Henry D.W.
      • Gaynon P.S.
      • Fu C.
      • Franklin J.
      • Siegel S.E.
      • et al.
      Obesity and outcome in pediatric acute lymphoblastic leukemia.
      • Lange B.J.
      • Gerbing R.B.
      • Feusner J.
      • Skilnik J.
      • Sacks N.
      • Smith F.O.
      • Alonza T.A.
      Mortality in overweight and underweight children with acute myeloid leukemia.
      Association between obesity and drug toxicity in children is unclear based on these retrospective studies. Large prospective studies would help to better elucidate the impact of obesity on clinical outcome in children with cancer. One must also consider the pharmacokinetics of chemotherapeutic agents in obese children, which are reviewed in the following discussion (Table III).

      Busulfan

      Busulfan is a hydrophilic drug that is minimally protein bound and primarily metabolized by the liver. It is given orally or intravenously in preparation for stem cell transplantation.
      AHFS Drug Information.
      Two retrospective studies described busulfan pharmacokinetics in obese children.
      Dupuis et al
      • Dupuis L.L.
      • Najdova M.
      • Saunders E.F.
      Retrospective appraisal of busulfan dose adjustment in children.
      conducted a retrospective cohort study to examine busulfan dosing in 38 children and found that busulfan doses adjusted to achieve a target AUC did not differ in children whose TBW was greater than their IBW (Table VII). An error in the busulfan gas chromatography assay that may have led to erroneously high concentrations was later reported.
      • Dupuis L.L.
      • Najdova M.
      • Saunders E.F.
      Retrospective appraisal of busulfan dose adjustment in children.
      Table VIISummary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of antineoplastic agents.
      Study and DesignDrug(s)PatientsMethodsResultsConclusions
      Dupuis et al,
      • Dupuis L.L.
      • Najdova M.
      • Saunders E.F.
      Retrospective appraisal of busulfan dose adjustment in children.
      retrospective cohort study
      • Busulfan
      • 38 children
      • 0.2–17.5 y (median, 5.7 y)
      • Oral or nasogastric busulfan 40 mg/m2 based on BSA calculated from TBW
      • Whole blood busulfan concentrations at 1, 1.5, and 6 hours
      • AUC calculated based on limited sampling strategy
      • Subsequent busulfan doses adjusted to achieve a target AUC 900–1400 μM/min
      • Adjusted busulfan dose was not different in children whose TBW was greater than their IBW
      • TBW is appropriate for initial busulfan dosing
      Browning et al,
      • Browning B.
      • Thormann K.
      • Donaldson A.
      • Halverson T.
      • Shinkle M.
      • Kletzel M.
      Busulfan dosing in children with BMIs ≥ 85% undergoing HSCT: a new optimal strategy.
      retrospective cohort study
      • Busulfan
      • 68 children and young adults
      • Aged 0–21 y (mean, 7.1 y), SCT preparation with busulfan and either fludarabine and rabbit ATG or extracorporeal photophoresis
      • 32% overweight (BMI ≥85th %)
      • Test dose busulfan 0.8 mg/kg TBW
      • Whole blood busulfan concentrations at 3, 3.5, 5, and 7 hours after start of test dose
      • Expected AUC for test dose 800–1200 μM/min. Further regimen doses based on pharmacokinetic parameters to achieve target AUC 4000 or 5000 μM/min
      • Compared busulfan dosing and AUC for overweight vs normal-weight children
      • Compared busulfan dosing based on PK vs package insert (dose based on ABW = IBW + 0.25(TBW – IBW)
      • Lower mean (SD) regimen doses per kilogram TBW for overweight vs normal-weight children (2.9 [1.1] vs 4.0 [1.1] mg/kg/d; P = 0.001)
      • No association between BMI and AUC being under or over target for test dose
      • Regimen dose based on PK vs package insert dose for overweight children achieved target AUC for 84% vs 47%
      • TBW is appropriate for the test dose; adjust regimen doses based on PK parameters
      • Dose based on ABW does not seem to achieve target AUC for overweight children
      Hijiya et al,
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      retrospective cohort study
      • Cytarabine
      • Etoposide
      • Methotrexate
      • Teniposide
      • 621 children
      • Aged >1 y, ALL treatment with cytarabine, methotrexate, teniposide, etoposide
      • 8.9% obese (BMI ≥95th %)
      • Chemotherapy doses based on BSA calculated by using TBW, then adjusted based on CL
      • Cytarabine 300 mg/m2
      • Etoposide 300 mg/m2
      • 6-Mercaptopurine PO 75 mg/m2
      • High-dose methotrexate 1500–5000 mg/m2
      • Teniposide 200–375 mg/m2
      • Compared safety, efficacy, and PK parameters between obese and normal-weight children
      • PK parameters derived from plasma–concentration time profiles by using noncompartmental analysis
      • CL calculated by multiplying Vd by ke
      • Mean cytarabine, etoposide, methotrexate, and teniposide CL not significantly different between obese and normal-weight children, after adjusting for known confounders including age (<10 y or ≥10 y), course of treatment, and study protocol
      • Cytarabine, etoposide, methotrexate, and teniposide doses based on BSA calculated using TBW are appropriate
      Thompson et al,
      • Thompson P.
      • Wheeler H.E.
      • Delaney S.M.
      • Lorier R.
      • Broeckel U.
      • et al.
      Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children’s Oncology Group.
      PK study
      • Daunorubicin
      • 98 children
      • Aged 1–21 y (median, 12 y), daunorubicin over 1 or 2 days as part of chemotherapy regimen
      • 16 obese children (BMI ≥95th %); 15 children with body fat >30%
      • Daunorubicin dosing not described
      • PK parameters derived from plasma–concentration time profiles using 2-compartment model for daunorubicin and 1-compartment model for daunorubicinol
      • Daunorubicin and daunorubicinol Vd (L/m2) and CL (L/h/m2) similar in obese vs normal-weight children
      • Daunorubicin and daunorubicinol Vd and CL similar in children with body fat <30% and >30%
      • Daunorubicin dose based on BSA calculated by using TBW seems appropriate
      Ritzmo et al,
      • Ritzmo C.
      • Soderhall S.
      • Karlen J.
      • Nygren H.
      • Eksborg S.
      Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient.
      case report
      • Doxorubicin
      • Etoposide
      • Morbidly obese 14 year-old boy (weight, 137 kg; height, 172 cm; BMI, 46.3 kg/m2; BSA, 2.56 m2) with Hodgkin’s lymphoma
      • Chemotherapy doses based on adjusted BSA 1.91 m2 (derived from the expected upper limit of weight for height)
      • Doxorubicin 40 mg/m2 (corresponding to 30 mg/m2 actual BSA) IV over 4 hours on days 1 and 15. Courses were separated by 2 weeks
      • Plasma concentrations of doxorubicin and its metabolite, doxorubicinol, immediately before end of infusion on day 1 of the first course and days 1 and 15 of the second course
      • Etoposide 125 mg/m2 (corresponding to 94 mg/m2 actual BSA) over 2 hours on days 3 to 7
      • Etoposide plasma concentrations on day 3 immediately before dosing and at 1, 2, 3, 6, and 12 hours after end of dosing
      • Doxorubicin and doxorubicinol plasma concentrations 202, 181, and 162 ng/mL and 11.8, 16.9, and 14.2 ng/mL, respectively
      • Median doxorubicin CL 476 mL/min/m2
      • Median etoposide CL 16.1 mL/min/m2 and t½ 3.6 hours
      • Doxorubicin CL is similar to reference values for normal-weight children
      • Etoposide CL and t½ are similar to reference values for normal-weight children
      Thompson et al,
      • Thompson P.A.
      • Rosner G.L.
      • Matthay K.K.
      • Moore T.B.
      • Bomgaars L.R.
      • Ellis K.J.
      • et al.
      Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study.
      PK study
      • Doxorubicin
      • 22 children
      • Aged 1–21 y (median, 15 y), doxorubicin over 1 or 2 days as part of chemotherapy regimen
      • 6 children with body fat >30%; 2 children overweight (BMI >85th %)
      • Doxorubicin dosed based on actual BSA
      • PK parameters derived from plasma–concentration time profiles by using noncompartmental analysis
      • Doxorubicin and doxorubicinol Vd (L/m2) and CL (L/h/m2) similar in overweight vs normal-weight children
      • Doxorubicin Vd and CL similar children with body fat <30% and >30%
      • Mean doxorubicinol Vd and CL higher in children with body fat >30% vs ≤30% (37.2 vs 64.8 L/h/m2; [P = 0.03] and (802 vs 1450 L/m2 [P = 0.02])
      • Doxorubicin dose based on BSA calculated by using TBW seems appropriate
      Sauer et al,
      • Sauer M.
      • Rydholm N.
      • Piatkowski J.
      • Lewis V.
      • Steiner M.
      Nephrotoxicity due to intermediate-dose methotrexate without rescue in an obese adolescent with acute lymphoblastic leukemia.
      case report
      • Methotrexate
      • 16-year-old obese boy (weight, 110 kg; height, 170 cm; BMI, 38.1 kg/m2) who received methotrexate as part of his ALL treatment
      • Initial methotrexate dose 100 mg/m2, based on calculated BSA of 2.3 m2 using TBW
      • Doses escalated to 250 mg/m2
      • Three days after the 250-mg/m2 dose, SCr was 2.8 mg/dL (baseline, 0.6 mg/dL) and GFR was 25 mL/min/1.73 m2
      • Renogram suggested acute tubular necrosis
      • Methotrexate concentration drawn 4 days after the dose was 2.9 μmol/L (supratherapeutic)
      • Folinic acid rescue and intravenous fluids containing sodium bicarbonate were administered, and the child improved
      • Role of obesity in development of nephrotoxicity is not clear
      ABW = adjusted body weight; ALL = acute lymphocytic leukemia; ATG = antithymocyte globulin; BMI = body mass index; BSA = body surface area; CL = clearance; GFR = glomerular filtration rate; IBW = ideal body weight; PK = pharmacokinetic; PO = orally; SCr = serum creatinine; SCT = stem cell transplantation; TBW = total body weight.
      Browning et al
      • Browning B.
      • Thormann K.
      • Donaldson A.
      • Halverson T.
      • Shinkle M.
      • Kletzel M.
      Busulfan dosing in children with BMIs ≥ 85% undergoing HSCT: a new optimal strategy.
      conducted a retrospective cohort study of 68 children receiving busulfan, 32% of whom were overweight (Table VII). Overweight children received lower regimen doses per kilogram TBW compared with children with a BMI in the 25th to 84th percentile. There was no association, however, between BMI and AUC being under or over target for the test dose.
      Limitations to these 2 studies
      • Dupuis L.L.
      • Najdova M.
      • Saunders E.F.
      Retrospective appraisal of busulfan dose adjustment in children.
      • Browning B.
      • Thormann K.
      • Donaldson A.
      • Halverson T.
      • Shinkle M.
      • Kletzel M.
      Busulfan dosing in children with BMIs ≥ 85% undergoing HSCT: a new optimal strategy.
      are inherent to the small sample size; the authors were not able to perform multivariate analysis or adjust for potential confounders such as drug interaction, age, and malignancy. From these studies, it seems that initial busulfan doses should be administered based on TBW (as opposed to IBW or ABW) for overweight or obese children (Table III). Pharmacokinetic analysis can help clinicians adjust subsequent doses to achieve target AUC.

      Cytarabine

      Hijiya et al
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      conducted a retrospective cohort study of 621 children (aged >1 year) who received treatment for ALL (Table VII). Cytarabine, methotrexate, and teniposide dosage was adjusted based on drug CL, and pharmacokinetic data were reported previously.
      • Evans W.E.
      • Relling M.V.
      • Rodman J.H.
      • Crom W.R.
      • Boyett J.M.
      • Pui C.H.
      Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia.
      • Wall A.M.
      • Gajjar A.
      • Link A.
      • Mahmoud H.
      • Pui C.H.
      • Relling M.V.
      Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia.
      • Relling M.V.
      • Hancock M.L.
      • Boyett J.M.
      • Pui C.H.
      • Evans W.E.
      Limited and optimal sampling strategies for etoposide and etoposide catechol in children with leukemia.
      Pharmacokinetic data were described for cytarabine, methotrexate, teniposide, and etoposide. Mean cytarabine CL was not significantly different between overweight, risk of overweight, and normal-weight children, after adjusting for known confounders including age (<10 years or ≥10 years), course of treatment, and study protocol. This study suggests that cytarabine can be dosed based on BSA calculated by using TBW. Results for methotrexate, teniposide, and etoposide are described later.

      Daunorubicin

      Thompson et al
      • Thompson P.
      • Wheeler H.E.
      • Delaney S.M.
      • Lorier R.
      • Broeckel U.
      • et al.
      Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children’s Oncology Group.
      studied daunorubicin pharmacokinetics in 98 children, 16 of whom were obese and 15 of whom had body fat >30% (Table VII). Daunorubicin and daunorubicinol Vd and CL were similar between obese and normal-weight children as well as for children with body fat >30%. Although the authors did not describe daunorubicin dosing, Vd and CL were expressed as a function of BSA. This study suggests that doxorubicin should be dosed based on BSA calculated by using TBW (Table III).

      Doxorubicin

      Ritzmo et al
      • Ritzmo C.
      • Soderhall S.
      • Karlen J.
      • Nygren H.
      • Eksborg S.
      Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient.
      reported on a morbidly obese boy with Hodgkin’s lymphoma who received treatment with doxorubicin and etoposide (Table VII). Doses were provided based on an adjusted BSA. Doxorubicin and doxorubicinol plasma concentration and doxorubicin CL were similar to those of normal-weight children from a previous study.
      • Eksborg S.
      • Palm C.
      • Bjork O.
      A comparative pharmacokinetic study of doxorubicin and 4-epi-doxorubicin in children with acute lymphoblastic leukemia using a limited sampling procedure.
      No toxicity was observed, and the patient’s ECG and echocardiography were normal at 2 months and 2 years after treatment. Based on the calculated doxorubicin CL, the dose based on BSA calculated by using his TBW would have been appropriate.
      Thompson et al
      • Thompson P.A.
      • Rosner G.L.
      • Matthay K.K.
      • Moore T.B.
      • Bomgaars L.R.
      • Ellis K.J.
      • et al.
      Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study.
      studied doxorubicin pharmacokinetics in 22 children, 2 of whom were overweight and 6 of whom had body fat >30% (Table VII). Doxorubicin and doxorubicinol Vd and CL were similar between overweight and normal-weight children. This study, although limited by the small number of overweight patients, also suggests that doxorubicin should be dosed based on BSA calculated by using TBW (Table III).

      Etoposide

      In the case report by Ritzmo et al,
      • Ritzmo C.
      • Soderhall S.
      • Karlen J.
      • Nygren H.
      • Eksborg S.
      Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient.
      etoposide was dosed based on an adjusted BSA. Etoposide CL and t½ were similar to previously published values for 16 normal-weight children.
      • Eksborg S.
      • Söderhäll S.
      • Frostvik-Stolt M.
      • Lindberg A.
      • Liliemark E.
      Plasma pharmacokinetics of etoposide (VP-16) after I.V. administration to children.
      In the retrospective cohort study by Hijiya et al
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      described earlier, there was no significant difference in mean etoposide CL between the overweight, risk of overweight, and normal-weight children. Both this study and the case report suggest that etoposide should be dosed based on BSA calculated by using TBW in obese children.

      Methotrexate

      Sauer et al
      • Sauer M.
      • Rydholm N.
      • Piatkowski J.
      • Lewis V.
      • Steiner M.
      Nephrotoxicity due to intermediate-dose methotrexate without rescue in an obese adolescent with acute lymphoblastic leukemia.
      published a case report of a 16-year-old obese boy who received intermediate-dose methotrexate as part of his treatment for ALL (Table VII). Three days after the 250-mg/m2 dose, the child developed renal injury. There have been similar reports of renal injury after administration of intermediate-dose methotrexate in normal-weight adults.
      • Stark A.N.
      • Jackson G.
      • Carey P.J.
      • Arfeen A.
      • Proctor S.J.
      Severe renal toxicity due to intermediate-dose methotrexate.
      Given that other risk factors for renal injury were not reported, the role of obesity in methotrexate toxicity is unclear in this case.
      In the retrospective cohort study by Hijiya et al,
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      there was no significant difference in mean CL of high-dose methotrexate between overweight, risk of overweight, and normal-weight children. This finding suggests that methotrexate should be dosed based on BSA calculated by using TBW. Monitoring clinically for signs of toxicity and measuring serum methotrexate concentrations as warranted seem reasonable.

      Teniposide

      In the retrospective cohort study by Hijiya et al,
      • Hijiya N.
      • Panetta J.C.
      • Zhou Y.
      • Kyzer E.P.
      • Howard S.C.
      • Jeha S.
      • et al.
      Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
      there was no significant difference in mean CL of teniposide between overweight, risk of overweight, and normal-weight children. This finding suggests that teniposide should be dosed based on BSA calculated using TBW.

      Antiviral Agents

      Delgado-Borrego et al
      • Delgado-Borrego A.
      • Healey D.
      • Negre B.
      • Christofi M.
      • Sabharwal S.
      • Ludwig D.A.
      • Chung R.T.
      • Jonas M.M.
      The influence of body mass index on outcome of pediatric chronic hepatitis C virus infection.
      conducted a retrospective cohort study of children and young adults who were treated with interferon for hepatitis C virus infection (Table II). The mean dose per kilogram TBW or percentage of patients receiving the maximum dose was not described. In multivariate analysis, adjusted for ribavirin use and genotype, higher baseline BMI z scores were associated with lower response to therapy. Currently, it is unclear if an alternative dosing strategy should be used for interferon in overweight children.

      Antihypertensive Agents

      Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

      Hanafy et al
      • Hanafy S.
      • Pinsk M.
      • Jamali F.
      Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease.
      conductive a retrospective cohort study of 48 children treated with an angiotensin II receptor blocker (ARB), an angiotensin-converting enzyme (ACE) inhibitor, or a calcium channel blocker (CCB) for hypertension associated with renal disease (Table VIII). The mean doses of medications were similar between groups. Obesity did not affect response to therapy in multivariate analyses. The small number of children receiving ACE inhibitors or ARBs is a limitation to this study; however, it suggests that obese and normal-weight children may have similar reductions in blood pressure when given the same dose of an ACE inhibitor or an ARB.
      Table VIIISummary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of antihypertensive agents.
      Study and DesignDrug(s)PatientsMethodsResultsConclusions
      Hanafy et al,
      • Hanafy S.
      • Pinsk M.
      • Jamali F.
      Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease.
      retrospective cohort study
      • ACE-I
      • ARB
      • CCB
      • 25 obese (BMI ≥95th % for age 2–18 y and weight ≥95th % for age <2 y) and 23 normal-weight children
      • Aged 0–18 y (mean, 8 y); ARB, ACE-I, or CCB for hypertension associated with renal disease
      • Compared response to therapy (responder defined as >10% reduction in systolic and/or diastolic blood pressure from baseline)
      • Multivariate analysis tested for covariates: age, sex, obesity, nephrotic syndrome and corticosteroid use
      • 8 children received ramipril; 7 children received other ACE-I or ARB
      • 9 children received amlodipine, 33 children received nifedipine
      • 9 children received combination ACE-I or ARB with CCB
      • Mean doses of ACE-Is, ARBs, or CCBs (mg/m2) similar in obese vs normal-weight
      • % reduction in SBP similar in obese vs normal-weight
      • Obesity did not affect response to ACE-I or ARB therapy in multivariate analysis
      • Obesity had a significant effect on SBP response (OR, 12.26 [CI, 1.2–122]) to CCB in the multivariate analysis
      • Obese children receiving similar mg/ m2 doses of ACE-Is or ARBs have similar response to therapy vs normal-weight children
      • Obese children receiving similar mg/ m2 doses of CCBs may have poorer response to therapy vs normal-weight children
      Meyers et al,
      • Meyers K.E.
      • Lieberman K.
      • Solar-Yohay S.
      • Han G.
      • Shi V.
      The efficacy and safety of valsartan in obese and non-obese pediatric hypertensive patients.
      post-hoc analysis of previous RCT
      • Valsartan
      • 142 obese (BMI ≥95th % or BMI z score ≥1.54) and 119 normal-weight children
      • Aged 6–16 y, weight ≥20 kg, MSSBP ≥95th % for age, sex, and height
      • RCT: randomized to low-, medium-, or high-dose valsartan for 2 weeks (subjects <35 kg received 10, 40, or 80 mg PO daily and those ≥35 kg received 20, 80, or 160 mg PO daily)
      • Post-hoc analysis compared valsartan dosing and response to therapy (target MSSBP defined as <95% for age, sex, and height)
      • Median (range) valsartan dose lower in obese vs normal-weight children (0.9 [0.3–4] mg/kg/d vs 1.7 [0.1–4.6] mg/kg/d; P value not reported)
      • Similar reductions in blood pressure in obese and normal-weight children
      • Target MSSBP achieved in 56% of obese and 44% of normal-weight children
      • Maximal BP reduction occurred at medium-dose for obese and high-dose for normal-weight children
      • Valsartan is similarly effective in obese vs normal-weight children despite lower doses per kilogram TBW
      ACE-I = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; BMI = body mass index; BP = blood pressure; CCB = calcium channel blocker; MSSBP = mean sitting systolic blood pressure; OR = odds ratio; PK = pharmacokinetic; RCT = randomized controlled trial; SBP = systolic blood pressure; TBW = total body weight.
      Meyers et al
      • Meyers K.E.
      • Lieberman K.
      • Solar-Yohay S.
      • Han G.
      • Shi V.
      The efficacy and safety of valsartan in obese and non-obese pediatric hypertensive patients.
      conducted a post-hoc analysis of their previous randomized, double-blind trial to compare the blood pressure–lowering effects of valsartan in obese and normal-weight children (Table VIII). Although the valsartan dose per kilogram TBW was lower in obese children compared with normal-weight children, similar reductions in blood pressure were achieved in obese and normal-weight children. Adverse events were similar between groups. This study suggests that valsartan is similarly effective in obese and normal-weight children, despite obese children receiving a lower dose per kilogram TBW. Valsartan could be initiated at low doses and titrated to effect in both normal-weight and obese children.
      These studies suggest that obese children have a blood pressure–lowering response to ACE inhibitors and ARBs similar to that of normal-weight children. Although there is limited information for ACE inhibitors, it seems that these medications should be dosed similarly in obese and normal-weight children. An empiric low starting dose can be used, and the medication can then be titrated to effect (Table V).

      Calcium Channel Blockers

      In the same study by Hanafy et al,
      • Hanafy S.
      • Pinsk M.
      • Jamali F.
      Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease.
      amlodipine, short-acting nifedipine, and long-acting nifedipine were prescribed. Mean doses of CCBs were similar between the obese and the normal-weight children (Table VIII). In multivariate analysis, obesity had a significant effect on systolic blood pressure response. Although this study was small, the results suggest that obese children may require higher doses of CCBs or other medications to achieve blood pressure control.

      Neuromuscular Blockers

      One dose–response study was available for the neuromuscular blocking agent succinylcholine.

      Rose JB, Theroux MC, Katz MS. The potency of succinylcholine in obese adolescents. Anesth Analg 200;90:576-8.

      Succinylcholine, an ionized drug, is rapidly metabolized in plasma by pseudocholinesterases to succinylmonocholine, which is eliminated renally.
      AHFS Drug Information.
      To determine the potency of succinylcholine, Rose et al

      Rose JB, Theroux MC, Katz MS. The potency of succinylcholine in obese adolescents. Anesth Analg 200;90:576-8.

      evaluated 30 obese children who received succinylcholine at doses of 100, 150, or 250 μg/kg TBW (Table I). The effective dose (ED) to depress 50% and 95% of muscle twitch (ED50 and ED95) were similar to those of 40 normal-weight children from a previous study.
      • Brown T.C.
      • Meretoja O.A.
      • Bell B.
      • Clare D.
      Suxamethonium—electromyographic studies in children.
      Succinylcholine had similar potency in obese and normal-weight children, and the authors suggest that it be dosed based on TBW. Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      suggested using ABW (cofactor of 0.8) to dose succinylcholine in critically ill obese children. In the study described earlier by Burke et al,
      • Burke C.N.
      • Voepel-Lewis T.
      • Wagner D.
      • Lau I.
      • Baldock A.
      • Malviya S.
      • Nafia O.
      A retrospective description of anesthetic medication dosing in overweight and obese children.
      obese children were more likely than normal-weight children to receive >10% less than the recommended dose of succinylcholine based on TBW.
      We found no dose–response or pharmacokinetic studies describing nondepolarizing neuromuscular blocking agents in obese children. Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      recommended that cisatracurium, pancuronium, and rocuronium be dosed by using ABW (cofactors of 0.2, 0.25, and 0.25, respectively) in critically ill obese children. This recommendation was based on studies in obese adults and the potential for accumulation with prolonged use if TBW is used for dosing. Neuromuscular blocking agent response can likely be monitored clinically to assist with determination of appropriate dosing in obese children. Indication, duration of use, and patient’s organ function should be considered when dosing these agents in obese children.

      Respiratory Agents

      Kwong and Jones
      • Kwong K.Y.
      • Jones C.A.
      Improvement of asthma control with omalizumab in 2 obese pediatric asthma patients.
      reported on 2 obese children who received omalizumab 375 mg SC every 2 weeks for moderate persistent asthma, despite there being no manufacturer-recommended dose based on their weight and immunoglobulin E level (Table IX). Both children had improvements in their asthma control, and both tolerated omalizumab. This case report suggests that obese children may still derive benefit from this drug.
      Table IXSummary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of miscellaneous medications.
      Study and DesignDrug(s)PatientsMethodsResultsConclusions
      Respiratory agents
       Kwong and Jones,
      • Kwong K.Y.
      • Jones C.A.
      Improvement of asthma control with omalizumab in 2 obese pediatric asthma patients.
      case report
      • Omalizumab
      • 2 obese children received omalizumab for moderate persistent asthma
      • Both receiving high-dose inhaled corticosteroid, long-acting β-agonist, and leukotriene receptor antagonist
      • Case 1: 14-year-old male; weight, 113 kg; IgE concentration, 459 U/mL
      • Case 2: 13-year-old male; weight, 120 kg; IgE concentration, 677 U/mL
      • Omalizumab 375 mg SC every 2 weeks
      • No manufacturer dosing for obese children
      • In first year, both children had reductions in asthma symptoms and in courses of oral steroids for exacerbations
      • Case 1: fluticasone dose reduced and achieved complete asthma control at the end of the first year
      • Obese children may benefit from omalizumab at maximum doses
      Vaccines
       Minana et al,
      • Minana J.S.
      • Ganuza M.G.
      • Millan P.F.
      • Fernandez M.P.
      Hepatitis B immunoresponsiveness in adolescents: a revaccination proposal after primary vaccination.
      prospective cohort study
      • Hepatitis B vaccine
      • 427 children
      • Mean age 12 y, hepatitis B vaccine
      • Obese children (BMI >90th %)
      • Hepatitis B vaccine 20 μg intramuscularly (into deltoid) at 0, 1, and 6 months.
      • Serum anti-HBs measured by radioimmunoassay 1 month after last immunization
      • Weak correlation between BMI and anti-HBs concentrations (r = –0.118; P = 0.015)
      • Median anti-HBs lower in obese vs normal-weight children (34,186 vs 47,186 IU/L)
      • All children had anti-HBs concentrations above the recommended level of 10 IU/L
      • Obese children may have lower antibody response to hepatitis B vaccine, but clinical significance is unclear
       Eliakim et al,
      • Eliakim A.
      • Swindt C.
      • Zaldivar F.
      • Casali P.
      • Cooper D.
      Reduced tetanus antibody titers in overweight children.
      retrospective cohort study
      • Tetanus vaccine
      • 15 overweight (BMI >85th %) and 15 normal-weight age-matched controls
      • Age 8–17 y (mean, 13 y), immunizations per parent report
      • Tetanus vaccine per parent report
      • Compared immunologic markers and tetanus antibodies between overweight and normal-weight children
      • Circulating TNF-α, IL1-β, IL1ra, IgM, IgA, IgG, IgG1, IgG2, IgG3, or IgG4 not significantly different in overweight vs normal-weight
      • Mean (SD) IL-6 concentration higher in overweight vs normal-weight children (2.6 [1.2] pg/mL vs 1.3 [1.2] pg/mL; P < 0.05)
      • Mean (SD) antitetanus IgG concentration lower in overweight vs normal-weight children (2.6 [2.3] IU/mL vs 4.2 [1.9] IU/mL; P < 0.05)
      • All children had anti-tetanus IgG concentrations above the recommended threshold of 0.1 IU/mL
      • Obese children may have lower antibody response to tetanus vaccine, but clinical significance is unclear
      Vitamin D
       Rajakumar et al,
      • Rajakumar K.
      • Fernstrom J.D.
      • Holick M.F.
      • Janosky J.E.
      • Greenspan S.L.
      Vitamin D status and response to vitamin D3 in obese vs. non-obese African American children.
      prospective cohort study
      • Vitamin D
      • 21 obese (BMI > 95th %) and 20 normal-weight (BMI 5th–75th %) children matched for age, sex, skin color, pubertal maturation
      • Aged 6–10 y, African American, vitamin D supplementation
      • Vitamin D3 400 IU daily for 1 month
      • Completed validated food questionnaire
      • Compared vitamin D status and response to supplementation in obese vs normal-weight children
      • 25(OH)D, 1,25(OH)2D, calcium, phosphorus, albumin, PTH, markers of bone formation, and resorption similar at baseline in obese versus normal-weight children
      • Proportion of vitamin D deficiency (serum 25[OH]D ≤20 ng/mL) and insufficiency (serum 25[OH]D >20 and <30 ng/mL) similar at baseline
      • Lower mean (SD) vitamin D intake in obese vs normal-weight children during the study period (218.1 [112] IU/d vs 339 [153] IU/d)
      • No significant difference in proportion of vitamin D deficiency or insufficiency, serum calcium, phosphorus, albumin, PTH, and bone-specific alkaline phosphatase after 1 month of vitamin D supplementation in obese versus normal-weight children
      • Obese children had similar vitamin D status and response to supplementation vs normal-weight children
       Mark et al,
      • Mark S.
      • Lambert M.
      • Delvin E.E.
      • O’Loughlin J.
      • Tremblay A.
      • Gray-Donald K.
      Higher vitamin D intake is needed to achieve serum 25(OH)D levels greater than 50 nmol/L in Quebec youth at high risk of obesity.
      prospective cohort study
      • Vitamin D
      • Aged 8–11 y (mean, 9.2 y), at risk of obesity (BMI ≥30 kg/m2 or waist circumference >88 cm for girls and 102 cm for boys)
      • 42% overweight (BMI ≥85th %)
      • Assessed physical measurements, including dual-energy x-ray absorptiometry for fat mass, dietary intake, and plasma 25(OH)D
      • Mean (SD) dietary intake of vitamin D was 6.6 (4.3) µg/d, which was below the recommended intake of 15 µg/d
      • 4% of children had plasma 25(OH)D ≤37.5 nmol/L, defined as hypovitaminosis D
      • % children with 25(OH)D ≤50 nmol/L and ≤75 nmol/L were 44.7% and 96.2%, respectively
      • Multivariate analysis: season, physical activity, and milk intake associated with plasma 25(OH)D, but fat mass was not associated with plasma 25(OH)D
      • Fat mass was not associated with plasma 25(OH)D
        Aguirre Castaneda et al,
      • Aguirre Castaneda R.
      • Nader N.
      • Weaver A.
      • Singh R.
      • Kumar S.
      Response to vitamin D3 supplementation in obese and non-obese Caucasian adolescents.
      prospective cohort study
      • Vitamin D
      • 18 obese (BMI ≥95th %) and 18 normal-weight (BMI, 5th–85th %) children matched for age, sex, and season
      • Aged 12–18 y; white; vitamin D supplementation
      • Vitamin D 2000 IU daily for 12 weeks
      • Compared vitamin D status and response to supplementation in obese vs normal-weight children
      • Baseline mean 25(OH)D lower in obese vs normal-weight children (25.2 vs 28.9 ng/mL; P = 0.029)
      • Baseline prevalence of vitamin D deficiency or insufficiency (25[OH]D <30 ng/mL) higher in obese versus normal-weight children (78% vs 61%)
      • Change in 25(OH)D lower in obese vs normal-weight children (5.8 vs 9.8 ng/mL; P = 0.019)
      • After supplementation, prevalence of vitamin D deficiency 50% in obese and 11% in normal-weight children
      • Obese children were more likely to have vitamin D deficiency and lower response to supplementation
      1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; anti-HBs = hepatitis B surface antigen antibodies; BMI = body mass index; Ig = immunoglobulin; IL = interleukin; PTH = parathyroid hormone; SC = subcutaneous; TNF = tumor necrosis factor.

      Vaccines

      Minana et al
      • Minana J.S.
      • Ganuza M.G.
      • Millan P.F.
      • Fernandez M.P.
      Hepatitis B immunoresponsiveness in adolescents: a revaccination proposal after primary vaccination.
      studied 427 children to examine hepatitis B vaccine immune response and duration of protection in obese versus normal-weight children (Table IX). There was a weak correlation between BMI and hepatitis B surface antigen antibodies; however, all children had concentrations of these antibodies above the recommended 10 IU/L.
      Eliakim et al
      • Eliakim A.
      • Swindt C.
      • Zaldivar F.
      • Casali P.
      • Cooper D.
      Reduced tetanus antibody titers in overweight children.
      studied 15 overweight and 15 normal-weight age-matched control subjects to examine response to childhood immunizations (Table IX). Timing of the last tetanus vaccine relative to the study was not provided. Antitetanus immunoglobulin G concentrations were significantly lower in overweight versus normal-weight children, but all children had antitetanus immunoglobulin G concentrations above the recommended threshold of 0.1 IU/mL.
      It seems that obese children may have a lower response to hepatitis B and tetanus immunization than normal children; however, the clinical significance of this finding is unclear given that obese children produce antibodies at concentrations well above the recommended threshold. Overweight and obese children should continue to receive the same immunizations as normal-weight children according to local guidelines.

      Vitamins and Minerals

      Rajakumar et al
      • Rajakumar K.
      • Fernstrom J.D.
      • Holick M.F.
      • Janosky J.E.
      • Greenspan S.L.
      Vitamin D status and response to vitamin D3 in obese vs. non-obese African American children.
      prospectively compared vitamin D status and response to supplementation during winter months in a cohort of 21 obese and 20 normal-weight African-American children (Table IX). Obese children had similar serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D concentrations at baseline compared with normal-weight children. After 1 month of vitamin D supplementation, there was no difference in proportion of vitamin D deficiency or insufficiency between obese and normal-weight children. To assess vitamin D status, Mark et al
      • Mark S.
      • Lambert M.
      • Delvin E.E.
      • O’Loughlin J.
      • Tremblay A.
      • Gray-Donald K.
      Higher vitamin D intake is needed to achieve serum 25(OH)D levels greater than 50 nmol/L in Quebec youth at high risk of obesity.
      conducted a prospective cohort study of children who were at risk of obesity. Fat mass was not associated with plasma 25(OH)D concentration. Aguirre Castaneda et al
      • Aguirre Castaneda R.
      • Nader N.
      • Weaver A.
      • Singh R.
      • Kumar S.
      Response to vitamin D3 supplementation in obese and non-obese Caucasian adolescents.
      conducted a prospective cohort study of obese and normal-weight white children. Prevalence of vitamin D insufficiency or deficiency was higher in obese children at baseline and after 12 weeks of vitamin D 2000 IU daily. The authors did not collect dietary vitamin D intake information, and adherence to treatment could not be adequately assessed.
      The impact of obesity on vitamin D status and response to supplementation in children is not clear from the aforementioned studies. Obese children may require larger doses of vitamin D supplementation; however, doses can be adjusted according to 25(OH)D concentrations.

      Conclusions

      From the available studies, it seems that TBW is an appropriate size descriptor for dosing antineoplastic agents, succinylcholine, and cefazolin. Obese children seem to require less heparin, enoxaparin, and warfarin per kilogram TBW than normal-weight children; however, providing standard adult doses may be insufficient. Obese children may also require less vancomycin and aminoglycosides per kilogram TBW than normal-weight children. For these medications, an alternate size descriptor in children has not been described, and initial dosing based on TBW and monitoring serum concentrations (vancomycin and aminoglycosides) or coagulation parameters (heparin, enoxaparin, and warfarin) may be appropriate. Obese children require less propofol than normal-weight children; however, there is limited information about dosing other anesthetics or opioids.
      Limitations to the available data include the inherent design constraints to case reports and retrospective cohort studies, as well as the small numbers of children in some studies. Use of normal-weight historical control subjects for obese children in the context of a pharmacokinetic study is not ideal. Although more information is becoming available, we are still limited in our understanding of pharmacokinetics in obese children. There is no pharmacokinetic information for opioids, benzodiazepines, antibiotics (eg, penicillins, carbapenems), antifungals, cardiac drugs (eg, digoxin, amiodarone), corticosteroids, or anticonvulsants. Limited information is available about drugs that are widely distributed into or can accumulate in adipose tissue. When dosing information is not available for obese children, it may be possible to extrapolate from available adult data, as has been described by Ross et al
      • Ross E.L.
      • Heizer J.
      • Mixon M.A.
      • Jorgensen J.
      • Valdez C.A.
      • et al.
      Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
      and Burke et al,
      • Burke C.N.
      • Voepel-Lewis T.
      • Wagner D.
      • Lau I.
      • Baldock A.
      • Malviya S.
      • Nafia O.
      A retrospective description of anesthetic medication dosing in overweight and obese children.
      but the effects of the child’s age on pharmacokinetics should be considered.

      Conflicts of Interest

      The authors have indicated that they have no conflicts of interest regarding the content of this article. The authors have received no support (past or present) from industry or organizations that might have influenced this work.

      Acknowledgments

      We confirm that all authors have read and approved the manuscript and that there are no other persons who satisfy the authorship criteria that are not listed. We confirm that the order of authors listed in the manuscript has been approved by all of us. The authors received no monetary support for the preparation of this article. Dr. Kendrick wrote the first draft of the manuscript and Dr. Carr wrote the first draft of the abstract. All authors were involved in revising the manuscript.

      References

        • WHO [homepage on the internet].
        Childhood overweight and obesity. 2013; ([cited Feb 12, 2015])
        • de Onis M.
        • Blossner M.
        • Borghi E.
        Global prevalence and trends of overweight and obesity among preschool children.
        Am J Clin Nutr. 2010; 92: 1257-1264
        • Ogden C.L.
        • Carroll M.D.
        • Kit B.K.
        • Flegal K.M.
        Prevalence of obesity and trends in body mass index among US children and adolescents, 1990-2010.
        JAMA. 2012; 307: 483-490
        • Gundogdu Z.
        Relationship between BMI and blood pressure in girls and boys.
        Public Health Nutr. 2008; 11: 1085-1088
        • Weiss R.
        • Kaufman F.R.
        Metabolic complications of childhood obesity.
        Diabetes Care. 2008; 31: S310-S316
        • Nathan B.M.
        • Moran A.
        Metabolic complications of obesity in childhood and adolescence: more than just diabetes.
        Curr Opin Endocrinol Diabetes Obes. 2008; 15: 21-29
        • Choudhary A.K.
        • Donnelly L.F.
        • Racadio J.M.
        • Strife J.L.
        Diseases associated with childhood obesity.
        AJR. 2007; 188: 1118-1130
        • Strauss R.S.
        Childhood obesity.
        Pediatr Clin North Am. 2002; 49: 175-201
        • Balakrisnan P.L.
        Identification of obesity and cardiovascular risk factors in childhood and adolescence.
        Pediatr Clin North Am. 2014; 61: 153-171
        • Biro F.M.
        • Khoury P.
        • Morrison J.A.
        Influence of obesity on timing of puberty.
        Int J Androl. 2006; 29: 272-277
        • Dunger D.B.
        • Ahmed M.L.
        • Ong K.K.
        Effects of obesity on growth and puberty.
        Best Pract Res Clin Endocrinol Metab. 2005; 19: 375-390
        • Janson B.
        • Thursky K.
        Dosing of antibiotics in obesity.
        Curr Opin Infect Dis. 2012; 25: 634-649
        • Lee J.B.
        • Winstead P.S.
        • Cook A.M.
        Pharmacokinetic alterations in obesity.
        Orthopedics. 2006; 29: 984-988
        • Casati A.
        • Putza M.
        Anesthesia in the obese patient: pharmacokinetic considerations.
        J Clin Anesth. 2005; 17: 134-145
        • Erstad B.L.
        Dosing of medications in morbidly obese patients in the intensive care unit setting.
        Intensive Care Med. 2004; 30: 18-31
        • Hall R.G.
        • Jean G.W.
        • Sigler M.
        • Shah S.
        Dosing considerations for obese patients receiving cancer chemotherapeutic agents.
        Ann Pharmacother. 2013; 47: 1666-1674
        • Sankaralingam S.
        • Kim R.B.
        • Padwal R.S.
        The impact of obesity on the pharmacology of medications used for cardiovascular risk factor control.
        Can J Cardiol. 2015; 31: 167-176
        • Hanley M.J.
        • Abernethy D.R.
        • Greenblatt D.J.
        Effect of obesity on the pharmacokinetics of drugs in humans.
        Clin Pharmacokinet. 2010; 49: 71-87
        • Kendrick J.G.
        • Carr R.R.
        • Ensom M.H.
        Pharmacokinetics and drug dosing in obese children.
        J Pediatr Pharmacol Ther. 2010; 15: 94-109
        • Mulla H.
        • Johnson T.N.
        Dosing dilemmas in obese children.
        Arch Dis Child Educ Pract Ed. 2010; 95: 112-117
        • Lobstein T.
        • Baur L.
        • Uauy R.
        International Obesity Task Force. Obesity in children and young people.
        Obes Rev. 2004; 5: 4-85
        • Krebs N.F.
        • Himes J.H.
        • Jacobson D.
        • Nicklas T.A.
        • Guilday P.
        • Styne D.
        Assessment of child and adolescent overweight and obesity.
        Pediatrics. 2007; 120: S193-S228
        • de Onis M.
        • Onyango A.
        • Van den Broeck J.
        • Chumlea W.
        • Martorell R.
        • for the WHO Multicentre Growth Reference Study Group
        Measurement and standardization protocols for anthropometric used in the construction of a new international growth reference.
        Food Nutrition Bull. 2004; 25: S27-S36
        • Freedman D.S.
        • Sherry B.L.
        The validity of BMI as an indicator of body fatness and risk among children.
        Pediatrics. 2009; 124: S23-S34
        • Wells J.C.
        • Fewtrell M.S.
        • Williams J.E.
        • Haroun D.
        • Lawson M.S.
        • Cole T.J.
        Body composition in normal weight, overweight, and obese children: matched case-control analyses of total and regional tissue masses, and body composition trends in relation to relative weight.
        Int J Obes. 2006; 30: 1506-1513
        • Battistini N.
        • Virgili F.
        • Severi S.
        • Brambilla P.
        • Manzoni P.
        • Beccaria L.
        • et al.
        Relative expansion of extracellular water in obese vs. normal children.
        J Appl Physiol. 1995; 79: 94-96
        • Bartelink I.H.
        • Rademaker C.M.
        • Schobbem A.F.
        • can den Anker J.N.
        Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations.
        Clin Pharmacokinet. 2006; 45: 1077-1097
        • Mosteller R.D.
        Simplified calculation of body-surface area.
        N Engl J Med. 1987; 317: 1098
        • Green B.
        • Duffull S.B.
        What is the best size descriptor to use for pharmacokinetic studies in the obese?.
        Br J Clin Pharmacol. 2004; 58: 119-133
        • Janmahasatian S.
        • Duffull S.B.
        • Ash S.
        • Ward L.C.
        • Byrne N.M.
        • Green B.
        Quantification of lean bodyweight.
        Clin Pharmacokinet. 2005; 44: 1051-1065
        • Phillips S.
        • Eldbeck A.
        • Kirby M.
        • et al.
        Ideal body weight in children.
        Nutr Clin Pract. 2007; 22: 240-245
        • Koshida R.
        • Nakashima E.
        • Taniguchi N.
        • Tsuji A.
        • Benet L.Z.
        • Ichimura F.
        Prediction of the distribution volumes of cefazolin and tobramycin in obese children based on physiological and pharmacokinetic concepts.
        Pharm Res. 1989; 6: 486-491
      1. AHFS Drug Information.
        in: McEvoy G.K. American Society of Health-System Pharmacists, Bethesda, Maryland2014
        • Burke C.N.
        • Voepel-Lewis T.
        • Wagner D.
        • Lau I.
        • Baldock A.
        • Malviya S.
        • Nafia O.
        A retrospective description of anesthetic medication dosing in overweight and obese children.
        Pediatric Anesthesia. 2014; 24: 857-862
        • Friedrichsdorf S.J.
        • Postier Nugent A.C.
        • Strobl A.Q.
        Codeine-associated pediatric deaths despite using recommended dosing guidelines: three case reports.
        J Opioid Management. 2013; 9: 151-155
        • Ross E.L.
        • Heizer J.
        • Mixon M.A.
        • Jorgensen J.
        • Valdez C.A.
        • et al.
        Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.
        Am J Health-Syst Pharm. 2015; 72: 542-556
        • Mortensen A.
        • Lenz K.
        • Abildstrom H.
        • Lauritsen T.L.
        Anesthetizing the obese child.
        Pediatr Anesthesia. 2011; 21: 623-629
        • Veyckemans F.
        Child obesity and anaesthetic morbidity.
        Curr Opin Anesthesiol. 2008; : 308-312
        • Samuels P.J.
        Anesthesia for adolescent bariatric surgery.
        Int Anesthesiol Clin. 2006; 44: 17-31
        • Smith H.L.
        • Meldrum D.J.
        • Brennan L.J.
        Childhood obesity: a challenge for the anaesthetist?.
        Paediat Anaesth. 2002; 12: 750-761
        • Olutoye O.A.
        • Yu X.
        • Govindan K.
        • Tija I.M.
        • East D.L.
        • Spearman R.
        • Garcia P.J.
        • et al.
        The effect of obesity on the ED95 of propofol for loss of consciousness in children and adolescents.
        Anesth Analg. 2012; 115: 147-153
        • Diepstraten J.
        • Chidambaran V.
        • Sadhasivam S.
        • Esslinger H.R.
        • Cox S.L.
        • Inge T.H.
        • Knibbe A.C.
        • et al.
        Propofol clearance in morbidly obese children and adolescents.
        Clin Pharmacokinet. 2012; 51: 543-551
        • Christian-Kopp S.
        • Sinha M.
        • Rosenberg D.I.
        • Eisendart A.W.
        • McDonald F.W.
        Antibiotic dosing for acute otitis media in children. A weighty issue.
        Pediatr Emerg Care. 2010; 26: 19-25
        • Lieberthal A.S.
        • Carroll A.E.
        • Chonmaitree T.
        • et al.
        American Academy of Pediatrics. Clinical Practice Guideline: The diagnosis and management of acute otitis media.
        Pediatrics. 2013; 131: e964-e969
        • Koshida R.
        • Nakashima E.
        • Ichimura F.
        • Nakano O.
        • Watanabe R.
        • Taniguchi N.
        • et al.
        Comparative distribution kinetics of cefazolin and tobramycin in children.
        J Pharmacobio-Dyn. 1987; 10: 436-442
        • Choi J.J.
        • Moffett B.S.
        • McDade E.J.
        • Palazzi D.L.
        Altered gentamicin serum concentrations in obese pediatric patients.
        Pediatr Infect Dis J. 2011; 30: 347-349
        • Taketomo C.K.
        • Hodding J.H.
        • Kraus D.M.
        Pediatric & Neonatal Dosage Handbook.
        19th ed. Lexi-Comp, Inc, Hudson, Ohio2012: 1143-1147
        • Moffett B.S.
        • Kim S.
        • Edwards M.S.
        Vancomycin dosing in obese pediatric patients.
        Clin Pediatr. 2011; 50: 442-446
        • Miller M.
        • Miller J.L.
        • Hagemann T.M.
        • Harrison D.
        • Chavez-Bueno S.
        • Johnson P.N.
        Vancomycin dosage in overweight and obese children.
        Am J Health-Syst Pharm. 2011; 68: 2062-2068
        • Heble D.E.
        • McPherson C.
        • Nelson M.
        • Hunstad D.A.
        Vancomycin trough concentration in overweight or obese pediatric patients.
        Pharmacotherapy. 2013; 33: 1273-1277
        • Moffett B.S.
        • Terula J.
        • Petit C.
        Heparin dosing in obese pediatric patients in the cardiac catheterization laboratory.
        Ann Pharmacother. 2011; 45: 876-880
        • Taylor B.N.
        • Bork S.J.
        • Kim S.
        • Moffett B.S.
        • Lee D.L.
        Evaluation of weight-based dosing of unfractionated heparin in obese children.
        J Pediatr. 2013; 163: 150-153
        • Lewis T.V.
        • Johnson P.N.
        • Nebbia A.M.
        • Dunlap M.
        Increased enoxaparin dosing is required for obese children.
        Pediatrics. 2011; 127: e787-e790
        • Richard A.A.
        • Kim S.
        • Moffett B.S.
        • Bomgaars L.
        • Mahoney D.
        • Yee D.L.
        Comparison of anti-Xa levels in obese and non-obese pediatric patients receiving treatment doses of enoxaparin.
        J Pediatr. 2013; 162: 293-296
        • Moffett B.C.
        • Bomgaars L.R.
        Response to warfarin therapy in obese pediatric patients dosed according to institutional guidelines.
        J Pediatr Hematol Oncol. 2014; 36: e487-e489
        • Sparreboon A.
        • Wolff A.C.
        • Mathijssen R.H.
        • Chatelut E.
        • Rowinsky E.K.
        • Verweij J.
        • et al.
        Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese.
        J Clin Oncol. 2007; 25: 4707-4713
        • Hunter R.J.
        • Navo M.A.
        • Thaker P.H.
        • Bodurka D.C.
        • Wolf J.K.
        • Smith J.A.
        Dosing chemotherapy in obese patients: actual versus assigned body surface area (BSA).
        Cancer Treat Rev. 2009; 35: 69-78
        • Griggs J.J.
        • Mangu P.B.
        • Anderson H.
        • et al.
        Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline.
        J Clin Oncol. 2012; 99: 1-10
        • Baillargeon J.
        • Langevin A.M.
        • Lewis M.
        • Thomas P.J.
        • Mullins J.
        • Dugan J.
        • et al.
        L-asparaginase as a marker of chemotherapy dose modification in children with acute lymphoblastic leukemia.
        Cancer. 2005; 104: 2858-2861
        • Inaba H.
        • Surprise H.C.
        • Pounds S.
        • Cao X.
        • Howard S.C.
        • Ringwald-Smith K.
        • Buaboonnam J.
        • Dahl G.
        • et al.
        Effect of body mass index on the outcome of children with acute myeloid leukemia.
        Cancer. 2012; 118: 5989-5996
        • Hijiya N.
        • Panetta J.C.
        • Zhou Y.
        • Kyzer E.P.
        • Howard S.C.
        • Jeha S.
        • et al.
        Body mass index does not influence pharmacokinetics or outcome of treatment of children with acute lymphoblastic leukemia.
        Blood. 2006; 108: 3997-4002
        • Gelelete C.B.
        • Pereira S.H.
        • Azevedo A.M.
        • Thiago L.S.
        • Mundim M.
        • Land M.G.
        • Costa E.S.
        Overweight as a prognostic factor in children with acute lymphoblastic leukemia.
        Obesity. 2011; 19: 1908-1911
        • Butturini A.M.
        • Dorey F.J.
        • Lange B.J.
        • Henry D.W.
        • Gaynon P.S.
        • Fu C.
        • Franklin J.
        • Siegel S.E.
        • et al.
        Obesity and outcome in pediatric acute lymphoblastic leukemia.
        J Clin Oncol. 2007; 25: 2063-2069
        • Lange B.J.
        • Gerbing R.B.
        • Feusner J.
        • Skilnik J.
        • Sacks N.
        • Smith F.O.
        • Alonza T.A.
        Mortality in overweight and underweight children with acute myeloid leukemia.
        JAMA. 2005; 291: 203-211
        • Dupuis L.L.
        • Najdova M.
        • Saunders E.F.
        Retrospective appraisal of busulfan dose adjustment in children.
        Bone Marrow Transplant. 2000; 26: 1143-1147
        • Dupuis L.L.
        • Najdova M.
        • Saunders E.F.
        Retrospective appraisal of busulfan dose adjustment in children.
        Bone Marrow Transplant. 2003; 31: 729
        • Browning B.
        • Thormann K.
        • Donaldson A.
        • Halverson T.
        • Shinkle M.
        • Kletzel M.
        Busulfan dosing in children with BMIs ≥ 85% undergoing HSCT: a new optimal strategy.
        Biol Blood Marrow Transplant. 2011; 17: 1383-1388
        • Evans W.E.
        • Relling M.V.
        • Rodman J.H.
        • Crom W.R.
        • Boyett J.M.
        • Pui C.H.
        Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia.
        N Engl J Med. 1998; 338: 499-505
        • Wall A.M.
        • Gajjar A.
        • Link A.
        • Mahmoud H.
        • Pui C.H.
        • Relling M.V.
        Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia.
        Leukemia. 2000; 14: 221-225
        • Relling M.V.
        • Hancock M.L.
        • Boyett J.M.
        • Pui C.H.
        • Evans W.E.
        Limited and optimal sampling strategies for etoposide and etoposide catechol in children with leukemia.
        J Pharmacokinet Pharmacodyn. 2002; 29: 171-188
        • Thompson P.
        • Wheeler H.E.
        • Delaney S.M.
        • Lorier R.
        • Broeckel U.
        • et al.
        Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children’s Oncology Group.
        Cancer Chemother Pharmacol. 2014; 74: 831-838
        • Ritzmo C.
        • Soderhall S.
        • Karlen J.
        • Nygren H.
        • Eksborg S.
        Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient.
        Pediatr Hematol Oncol. 2007; 24: 437-445
        • Eksborg S.
        • Palm C.
        • Bjork O.
        A comparative pharmacokinetic study of doxorubicin and 4-epi-doxorubicin in children with acute lymphoblastic leukemia using a limited sampling procedure.
        Anti-Cancer Drugs. 2000; 11: 129-136
        • Thompson P.A.
        • Rosner G.L.
        • Matthay K.K.
        • Moore T.B.
        • Bomgaars L.R.
        • Ellis K.J.
        • et al.
        Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study.
        Cancer Chemother Pharmacol. 2009; 64: 243-251
        • Eksborg S.
        • Söderhäll S.
        • Frostvik-Stolt M.
        • Lindberg A.
        • Liliemark E.
        Plasma pharmacokinetics of etoposide (VP-16) after I.V. administration to children.
        Anticancer Drugs. 2000; 11: 237-241
        • Sauer M.
        • Rydholm N.
        • Piatkowski J.
        • Lewis V.
        • Steiner M.
        Nephrotoxicity due to intermediate-dose methotrexate without rescue in an obese adolescent with acute lymphoblastic leukemia.
        Pediatr Hematol Oncol. 2002; 19: 135-140
        • Stark A.N.
        • Jackson G.
        • Carey P.J.
        • Arfeen A.
        • Proctor S.J.
        Severe renal toxicity due to intermediate-dose methotrexate.
        Can Chemother Pharm. 1989; 24: 243-245
        • Delgado-Borrego A.
        • Healey D.
        • Negre B.
        • Christofi M.
        • Sabharwal S.
        • Ludwig D.A.
        • Chung R.T.
        • Jonas M.M.
        The influence of body mass index on outcome of pediatric chronic hepatitis C virus infection.
        J Pediatr Gastroenterol Nutr. 2010; 51: 191-197
        • Hanafy S.
        • Pinsk M.
        • Jamali F.
        Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease.
        Pediatr Nephrol. 2009; 24: 815-821
        • Meyers K.E.
        • Lieberman K.
        • Solar-Yohay S.
        • Han G.
        • Shi V.
        The efficacy and safety of valsartan in obese and non-obese pediatric hypertensive patients.
        J Clin Hypertens (Greenwich). 2011; 13: 758-766
      2. Rose JB, Theroux MC, Katz MS. The potency of succinylcholine in obese adolescents. Anesth Analg 200;90:576-8.

        • Brown T.C.
        • Meretoja O.A.
        • Bell B.
        • Clare D.
        Suxamethonium—electromyographic studies in children.
        Anaesth Intens Care. 1990; 18: 473-476
        • Kwong K.Y.
        • Jones C.A.
        Improvement of asthma control with omalizumab in 2 obese pediatric asthma patients.
        Ann Allergy Immunol. 2006; 97: 288-293
        • Minana J.S.
        • Ganuza M.G.
        • Millan P.F.
        • Fernandez M.P.
        Hepatitis B immunoresponsiveness in adolescents: a revaccination proposal after primary vaccination.
        Vaccine. 1996; 14: 103-106
        • Eliakim A.
        • Swindt C.
        • Zaldivar F.
        • Casali P.
        • Cooper D.
        Reduced tetanus antibody titers in overweight children.
        Autoimmunity. 2006; 39: 137-141
        • Rajakumar K.
        • Fernstrom J.D.
        • Holick M.F.
        • Janosky J.E.
        • Greenspan S.L.
        Vitamin D status and response to vitamin D3 in obese vs. non-obese African American children.
        Obesity. 2008; 16: 90-95
        • Mark S.
        • Lambert M.
        • Delvin E.E.
        • O’Loughlin J.
        • Tremblay A.
        • Gray-Donald K.
        Higher vitamin D intake is needed to achieve serum 25(OH)D levels greater than 50 nmol/L in Quebec youth at high risk of obesity.
        Eur J Clin Nutr. 2011; 65: 486-492
        • Aguirre Castaneda R.
        • Nader N.
        • Weaver A.
        • Singh R.
        • Kumar S.
        Response to vitamin D3 supplementation in obese and non-obese Caucasian adolescents.
        Horm Res Paediatr. 2012; 78: 226-231