Abstract
Purpose
Approximately 1 of 6 children in the United States is obese. This has important implications for drug dosing and safety because pharmacokinetic (PK) changes are known to occur in obesity due to altered body composition and physiologic mechanisms. Inappropriate drug dosing in an emergency setting can limit therapeutic efficacy and increase drug-related toxic effects for obese children. Few systematic reviews examining PK properties and drug dosing in obese children have been performed.
Methods
We identified 25 emergency care drugs from the Strategic National Stockpile and Acute Care Supportive Drugs List and performed a systematic review for each drug in 3 study populations: obese children (2–18 years of age), normal weight children, and obese adults (aged >18 years). For each study population, we first reviewed a drug’s Food and Drug Administration label and then performed a systematic literature review. From the literature, we extracted drug PK data, biochemical properties, and dosing information. We then reviewed data in 3 age subpopulations (2–7 years, 8–12 years, and 13–18 years) for obese and normal weight children and by route of drug administration (intramuscular, intravenous, oral, and inhaled). If sufficient PK data were not available by age and route of administration, a data gap was identified.
Findings
Only 2 of 25 emergency care drugs (8%) contained dosing information on the Food and Drug Administration label for obese children and adults compared with 22 of 25 (88%) for normal weight children. We found no sufficient PK data in the literature for any of the emergency care drugs in obese children. Sufficient PK data were found for 7 of 25 emergency care drugs (28%) in normal weight children and 3 of 25 (12%) in obese adults.
Implications
Insufficient information exists to guide dosing in obese children for any of the emergency care drugs reviewed. This knowledge gap is alarming, given the known PK changes that occur in the setting of obesity. Future clinical trials examining the PK properties of emergency care medications in obese children should be prioritized.
Key words
Introduction
Childhood obesity has reached epidemic proportions in the United States.
1
, 2
, 3
Approximately 1 of 6 US children or adolescents has a body mass index for age and sex >95th percentile and is considered obese.2
Since 1980, the prevalence of childhood obesity has nearly tripled.3
Obese children require more frequent and more complex medical interventions given their increased rate and severity of multiple disease states.4
, 5
, 6
, 7
, 8
, 9
Obesity changes body composition and physiologic mechanisms: obese persons have increases in lean body mass,
10
fat mass,11
and proportion of extracellular water to total body water.12
Obesity also increases blood volume,13
cardiac output,14
and renal blood flow.15
, 16
These changes can alter pharmacokinetic (PK) parameters, such as Vd, clearance (CL), and drug absorption,17
, 18
, 19
resulting in important implications for drug dosing and tolerability in obese children.Dosing obese individuals using traditional body size measurements or drug physiochemical profiles is unreliable.
20
Reduced survival in obese children after cardiopulmonary resuscitation may be a result of these suboptimal dosing strategies.21
Conversely, inappropriately high drug dosing for obese children could result in significant toxic effects. Dosing epinephrine by total weight during a cardiac arrest in an obese child, for example, could result in an overdose given its linear PK properties.22
Few systematic reviews examining PK properties and drug dosing in obese children have been performed,
20
, 23
, 24
and all have concluded that more information is needed to effectively dose obese children. In an emergency setting, many commonly used drugs administered by weight may be dosed inaccurately resulting in therapeutic failure or significant toxicity, and possibly death. We aimed to determine which drugs used in pediatric emergency care have been adequately studied or labeled for use in obese children.Methods
We identified 25 emergency care drugs from the Strategic National Stockpile
25
and Acute Care Supportive Drugs List.Strategic National Stockpile (SNS). http://www.cdc.gov/phpr/stockpile/stockpile.htm. Accessed June 5, 2015.
26
The Strategic National Stockpile is a national repository of medicine and medical supplies managed by the Centers for Disease Control and Prevention for use in public health emergencies. The Acute Care Supportive Drugs List is managed by the Chemical Hazards Emergency Medical Management website for use by health care professionals in the setting of a mass-casualty incident. We identified emergency care drugs for review on the basis of their frequency of use and potential indication for children in a national emergency.Key emergency care pediatric medications. http://chemm.nlm.nih.gov/pediatricmedications.htm. Accessed June 5, 2015.
We performed a systematic review of available data for each drug. Each step of the review process was performed by one reviewer and verified by another reviewer with the necessary expertise in data management, PK analysis, drug development, and regulatory affairs.
First, we reviewed each drug’s Food and Drug Administration (FDA) label for dosing and indication information for 3 study populations: obese children (2–18 years of age), normal weight children, and obese adults (aged >18 years). On the basis of the findings from this review, each drug was sorted into one of the following categories: (1) dosing information and indication in study population provided on label, (2) dosing recommendation without indication in study population provided on label, or (3) neither dosing recommendation nor indication in study population provided on label.
Second, we conducted a systematic literature review for each drug in the 3 study populations. We selected peer-reviewed articles from PubMed and Embase using a uniform search strategy defined in collaboration with librarians at Duke University Medical Center Library and the National Library of Medicine. We included the following search terms: pharmacokinetics, pharmacodynamics, medication, dosing, dose, dosage, overweight, obesity, and obese. From the literature, we extracted drug PK data, biochemical properties, and dosing information, as well as basic study characteristics (sample size, number of PK samples per patient, and analysis type [eg, population PK properties, noncompartmental analysis]).
Third, we reviewed all collected data for each drug separately in the following subpopulations: obese children aged 2 to 7 years, obese children aged 8 to 12 years, obese children aged 13 to 18 years, nonobese children aged 2 to 7 years, nonobese children aged 8 to 12 years, nonobese children aged 13 to 18 years, and obese adults (aged >18 years). When applicable, we further stratified drugs by route of administration (intramuscular, intravenous, oral, and, rarely, inhaled). We considered data in each category sufficient for current dosing recommendations if PK parameters (Vd, CL, and half-life) were known and derived from data in at least 6 individuals in a defined age group. A data gap was identified if no PK parameters were identified or there were <6 individuals in a defined age group.
Results
The results of our FDA label review for all 25 emergency care drugs in each of the 3 study populations are summarized in Table I. Of the 25 drugs, only acyclovir and gentamicin had dosing information for obese children in the FDA label. The label for acyclovir recommends dosing obese children based on ideal weight. The label for gentamicin recommends dosing obese children based on lean body mass. Categorization of the emergency care drugs based on dosing and indication information provided is summarized in Table II.
Table IFood and Drug Administration label review of priority drugs.
| Dosing | Indication | ||||||
| Drug Class | Drug Name | Obese Children | Normal Weight Children | Obese Adults | Obese Children | Normal Weight Children | Obese Adults |
| Antibiotic | Amoxicillin-clavulanate | x | x | ||||
| Ceftazidime | x | ||||||
| Cidofovir | |||||||
| Ciprofloxacin | x | x | |||||
| Gentamicin | x | x | x | ||||
| Levofloxacin | x | x | |||||
| Raxibacumab | x | x | |||||
| Antifungal | Amphotericin | x | |||||
| Fluconazole | x | x | |||||
| Antiviral | Acyclovir | x | x | x | x | ||
| Oseltamivir | x | x | |||||
| Probenacid | x | ||||||
| Rimantadine | x | x | |||||
| Zanamivir | x | x | |||||
| Chemical | Sodium thiosulfate | x | |||||
| Radiation | Calcium diethylenetriamine penta-acetate | x | |||||
| Neupogen | |||||||
| Prussian blue | x | ||||||
| Zinc diethylenetriamine penta-acetate | x | ||||||
| Supportive | Calcium chloride | x | x | ||||
| Diphenhydramine | x | ||||||
| Ipratropium | x | x | |||||
| Magnesium sulfate | x | x | |||||
| Oxycodone/acetaminophen | |||||||
| Promethazine | x | x | |||||
* Gentamicin dosing is by lean weight. Acyclovir dosing is by ideal weight.
Table IIDrug categories.
| No. (%) of Study Participants | |||
| Category | Obese Children | Normal Weight Children | Obese Adults |
| Dosing and indication | 0/25 | 13/25 (52) | 0/25 |
| Dosing | 2/25 (8) | 9/25 (36) | 2/25 (8) |
| Neither | 23/25 (92) | 3/25 (12) | 23/25 (92) |
The numbers of individuals for which PK data are available for each age and route of administration are provided in Table III. We found no sufficient PK data for any of the emergency care drugs in obese children. We found sufficient PK data for 7 of 25 emergency care drugs (28%) in normal weight children: intravenous ceftazidime for children aged 2 to 12 years, oral ciprofloxacin for children aged 2 to 18 years, intravenous ciprofloxacin for children aged 13 to 18 years, intravenous gentamicin for children aged 2 to 18 years, intravenous and oral levofloxacin for children aged 2 to 12 years, intravenous amphotericin for children aged 2 to 7 years, oral acyclovir for children aged 2 to 7 years, and oral oseltamivir for children aged 2 to 18 years. We found sufficient PK data for 3 of 25 emergency care drugs (12%) in obese adults: intravenous ceftazidime, intravenous levofloxacin, and oral oseltamivir.
Table IIIEmergency care drug gaps.
| Study Population | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Obese Children | Normal Weight Children | Obese Adults | |||||||
| Drug Class | Drug Name | Route of Administration | 2–7 YEARS | 8–12 YEARS | 13–18 YEARS | 2–7 YEARS | 8–12 YEARS | 13–18 YEARS | (>18 Years) |
| Antibiotic | Amoxicillin-clavulanate | PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Ceftazidime | IM | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| IV | 0 | 0 | 0 | 16 | 13 | 0 | 49 | ||
| Cidofovir | IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Ciprofloxacin | IV | 0 | 0 | 0 | 0 | 0 | 7 | 0 | |
| PO | 0 | 0 | 0 | 16 | 6 | 12 | 0 | ||
| Gentamicin | IM | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| IV | 0 | 0 | 0 | 92 | 24 | 20 | 0 | ||
| Levofloxacin | IV | 0 | 0 | 0 | 7 | 7 | 0 | 25 | |
| PO | 0 | 0 | 0 | 8 | 8 | 0 | 0 | ||
| Raxibacumab | IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Antifungal | Amphotericin | IV | 0 | 0 | 0 | 7 | 0 | 0 | 0 |
| Fluconazole | IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Antiviral | Acyclovir | IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PO | 0 | 0 | 0 | 16 | 0 | 0 | 0 | ||
| Oseltamivir | PO | 0 | 0 | 0 | 14 | 8 | 8 | 72 | |
| Probenacid | PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Rimantadine | PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Zanamivir | INH | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Chemical | Sodium thiosulfate | IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Radiation | Calcium diethylenetriamine penta-acetate | IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Neupogen | IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Prussian blue | PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Zinc diethylenetriamine penta-acetate | IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Supportive | Calcium chloride | IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Diphenhydramine | IM | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Ipratropium | INH | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Magnesium sulfate | IM | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Oxycodone/acetaminophen | PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Promethazine | IM | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| IV | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| PO | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
IM = intramuscular; INH = inhaled; IV = intravenous; PO = oral.
Discussion
The lack of sufficient data to guide emergency care drug dosing in obese children is alarming. Federal legislation and the FDA require that drugs be tested for tolerability and efficacy. Before most drugs are approved for clinical use, they must be tested in the specified population, at the specified dose, and for a specified amount of time. Clinical, ethical, and logistical challenges have prevented the testing of many drugs in children. This has led to the common use of off-label or unauthorized drugs in children,
22
, 23
, 24
, 25
, Strategic National Stockpile (SNS). http://www.cdc.gov/phpr/stockpile/stockpile.htm. Accessed June 5, 2015.
26
, Key emergency care pediatric medications. http://chemm.nlm.nih.gov/pediatricmedications.htm. Accessed June 5, 2015.
27
, 28
which has been associated with an increased incidence in adverse drug reactions.29
, 30
The Best Pharmaceuticals for Children Act, established in 2002 and most recently renewed in 2012, provides mechanisms for studying on- and off-patent drugs in children and has established a program for pediatric drug development through the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Despite this legislation, obese children remain largely understudied.Given the prevalence of childhood obesity, the paucity of PK data in this population is concerning. A systematic review of PK studies in obese children was conducted in 2014 and found only 20 studies (21 drugs) during 40 years.
23
Although many studies reported important obesity-related changes in PK properties, they were limited by small sample sizes, and many of the drugs were not commonly prescribed agents. A review in 2010 found only 10 drugs with available PK data in obese children and concluded that extrapolation from adult data could be made if the effects of a child’s growth and development on PK parameters were considered.31
However, simple extrapolation from adult studies is inaccurate when attempting to predict CL and other PK parameters in children due to maturational differences surrounding enzyme expression and activity, as well as drug elimination and metabolizing pathways.32
PK alterations occur in the setting of obesity secondary to changes in body composition and physiology. Obese children have increased lean body mass
10
; fat-free mass; fat mass or mineral11
, 27
; extracellular water proportion12
; and drug-metabolizing enzymatic activity.28
In adults, obesity increases blood volume,12
cardiac output,13
and renal blood flow.14
, 15
Although increased cardiac output and alterations in enterohepatic circulation increase drug absorption in obesity,29
other studies suggest that absorption is not significantly altered in the setting of obesity.19
The principle PK parameter altered in obesity is Vd,
30
, 31
, 32
which is determined by the physiochemical properties of a drug, such as lipophilicity and protein binding.30
Studies have found that hydrophilic compounds should be dosed according to ideal weight, given their relatively small Vd.33
, 34
, 35
This finding can be explained by the premise that hydrophilic compounds are expected to remain in the intravascular space and bind less to adipose tissue, making their Vd lower and potentially placing children at risk for overdose. In contrast, there is an expected affinity of lipophilic compounds to adipose tissue, making their Vd higher and potentially necessitating increased dosing. This association between a drug’s lipophilicity and its distribution to adipose tissue is not consistent with certain highly lipophilic drugs. For example, a study found that β-blockers bind with greater affinity to lean tissue rather than adipose tissue.36
Overall, lipophilic compounds seem to have much greater PK variability in obese individuals and should not be dosed with only physicochemical properties in mind.36
, 37
Altered metabolic activity can occur as result of fatty infiltration of the liver in obese individuals,33
although this has been difficult to study.19
In addition, the increased size, perfusion, and glomerular filtration17
of the kidneys seen in obesity may alter renal elimination.16
Body size measurements have been used in the absence of dosing recommendations in obese children. Unlike their normal weight counterparts, who are typically dosed by total weight in kilograms, other measurements, such as ideal weight, lean body mass, and body surface area, have been used to better correlate with Vd and CL to achieve a more accurate and desired exposure.
30
However, a study evaluating the PK properties of antimicrobials in obese children concluded that traditional body size measures used for drug dosing in obese children do not account for potential changes in CL mechanisms, such as drug-metabolizing enzyme activity and renal function.20
Previously, drug LogP or partition coefficient, a measure of lipophilicity, was considered an important determinant of drug distribution in obese patients,
17
but it was recently found that PK alterations in obesity were not predicted by this or the Biopharmaceutics Drug Disposition Classification System.23
The Biopharmaceutics Drug Disposition Classification System takes into consideration both the extent of metabolism and solubility and may help predict routes of elimination, the role of drug transporters in the gut and liver, and the transporter-enzyme interplay.38
Although the analysis was limited by a small amount of PK data, it seems that Vd and CL in obese children are affected by other drug-specific factors, such as metabolic pathways and routes of absorption and elimination.23
The known alterations that occur in obese individuals have the potential to result in inappropriate drug dosing, which can limit therapeutic efficacy. For example, obese children who experience a cardiac arrest are 25% more likely to die than are their nonobese counterparts. Although this increase in mortality is likely multifactorial,
21
inappropriate dosing is likely to be an important component. Several examples include the following: (1) use of the Broselow tape has resulted in underdosing of select drugs such as amiodarone39
; (2) obese children had a decreased response to calcium channel blockers when provided similar dosing in milligrams per square meters40
; and (3) dosing based on actual weight for an obese patient during a cardiac arrest can also result in significant overdosing (eg, epinephrine).22
Obesity is a risk factor for antibiotic treatment failure that may result from a one-size-fits-all dosing strategy.
41
In a comprehensive PK review of antibiotic dosing in adults, it was found that modifications in Vd and CL generally result in less-than-optimal drug concentrations in the blood and tissue for the most commonly prescribed antibiotic classes and indications.42
Although extrapolation from adult studies has proven to be inaccurate for children,32
the PK changes known to occur in obese children make antibiotic treatment failure a plausible and important consideration when dosing antibiotics.Overall, we found significant data gaps for most emergency care drugs in our review, with obese children being the population most affected. None of the emergency care drugs we chose have been adequately studied or labeled for appropriate use in obese children—a knowledge gap that is alarming and has important implications because obesity has reached epidemic proportions. Future clinical trials examining the PK properties of emergency care medications in obese children should be prioritized.
Funding Sources
This work was funded under contract HHSN275201000003I from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for the Pediatric Trials Network. Research reported in this publication was also supported by award UL1TR001117 from the National Center for Advancing Translational Sciences of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflicts of Interest
Dr Benjamin receives support from the National Institutes of Health (award 2K24HD058735-06), National Center for Advancing Translational Sciences (award UL1TR001117), National Institute of Child Health and Human Development (contract HHSN275201000003I), and National Institute of Allergy and Infectious Diseases (contract HHSN272201500006I); he also receives research support from Cempra Pharmaceuticals (subaward to HHSO100201300009C) and industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). The authors have indicated that they have no other conflicts of interest regarding the content of this article.
Acknowledgments
Dr Rowe drafted and revised the manuscript. Dr Siegel and Dr Benjamin both reviewed the manuscript and provided critical feedback. All authors approved the final manuscript for submission. The members of the Pediatric Trials Network Administrative Core Committee are as follows: Katherine Y. Berezny, Duke Clinical Research Institute, Durham, NC; Edmund Capparelli, University of California–San Diego, San Diego, CA; Michael Cohen-Wolkowiez, Duke Clinical Research Institute, Durham, NC; Gregory L. Kearns, Children’s Mercy Hospital, Kansas City, MO; Matthew Laughon, University of North Carolina at Chapel Hill, Chapel Hill, NC; Andre Muelenaer, Virginia Tech Carilion School of Medicine, Roanoke, VA; T. Michael O’Shea, Wake Forest Baptist Medical Center, Winston Salem, NC; Ian M. Paul, Penn State College of Medicine, Hershey, PA; P. Brian Smith, Duke Clinical Research Institute, Durham, NC; John van den Anker, George Washington University School of Medicine and Health, Washington, DC; Kelly Wade, Children’s Hospital of Philadelphia, Philadelphia, PA; Thomas J. Walsh, Weill Cornell Medical College of Cornell University, New York, NY. The Eunice Kennedy Shriver National Institute of Child Health and Human Development: Perdita Taylor-Zapata, Anne Zajicek, Alice Pagan. The Emmes Corporation (Data Coordinating Center): Ravinder Anand, Gina Simone.
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Strategic National Stockpile (SNS). http://www.cdc.gov/phpr/stockpile/stockpile.htm. Accessed June 5, 2015.
Key emergency care pediatric medications. http://chemm.nlm.nih.gov/pediatricmedications.htm. Accessed June 5, 2015.
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Article info
Publication history
Published online: August 28, 2015
Accepted:
August 13,
2015
Identification
Copyright
© 2015 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
