Clinical Therapeutics

Velaglucerase Alfa for the Management of Type 1 Gaucher Disease

Jennifer L. Morris — 2012-01-24

Abstract: Background: Gaucher disease (GD) is the most common lysosomal storage disease, (frequency of 1:40,000 to 1:60,000). Ninety-Five percent of patients have type 1 (nonneuropathic type). Symptomatic patients with type 1 GD are treated with enzyme replacement therapy (ERT) to improve disease-induced effects on hemoglobin, platelets, and liver and spleen volume. Currently, several ERTs are available. Objective: The goal of this article was to review the pharmacology, efficacy, and safety data available for the use of a recently approved ERT, velaglucerase alfa, for the treatment of type 1 GD in symptomatic pediatric and adult patients. Methods: Serial searches of MEDLINE, EMBASE, and Cochrane databases for English-language, peer-reviewed, clinical data (using the search term velaglucerase alfa) were completed, with the final search in November 2011. All identified, peer-reviewed published human data were used for this review. Due to minimal peer-reviewed published data, those data reported via clinical trial registries or in the form of published abstracts were included. The manufacturer was contacted and given the opportunity to submit supplemental data for consideration of inclusion by the author. Results: Velaglucerase alfa is produced through gene activation technology and is identical to wild-type enzyme. As with other ERTs for type 1 GD, velaglucerase alfa targets accumulated glucocerebroside primarily within the lysosome of the macrophages in the affected organs and systems. When administered at doses of 60 U/kg intravenously, velaglucerase alfa follows linear pharmacokinetics and is rapidly eliminated, with a mean (SD) residence time or time for 63% of the dose to be cleared from systemic circulation of 14 (4) minutes. Four trials and early access program data reporting efficacy were identified for this review: 5 peer-reviewed publications, 3 clinical trial registry reports, and 1 abstract-only publication. Phase I/II data with an extension phase (n = 12) showed significant improvements (all, P < 0.004) in hemoglobin concentrations (21.7%), platelet counts (157.8%), and hepatic (−42.8%) and spleen (−79.3%) volumes at 48 months. Bone mineral density data reported out to 69 months for this extension population noted significant improvements in z score slope for both lumbar spine (0.14 z score unit per year; P < 0.01) and femoral head (0.08 z score unit per year; P < 0.01). Benchmarking of 7 patients with complete clinical datasets at 57 months identified achievement and maintenance of therapeutic goals set by the International Collaborative Gaucher Group for anemia, platelet counts, hepatosplenomegaly, and bone mineral density. Thirty-eight patients enrolled in an open-label, therapy-switch trial who received velaglucerase alfa at doses consistent with current doses of imiglucerase maintained hemoglobin (−0.101 g/dL [95% CI, −0.272 to 0.07]) and platelet counts (7.04% [95% CI, 0.54% to 13.53%]) at 53 weeks after therapy change. Phase III data evaluating 2 dosing regimens of velaglucerase alfa 60 and 45 U/kg intravenously every other week reported significant improvements in most measured clinical parameters at 12 months: hemoglobin concentrations (60 U/kg, 2.429 [0.324] g/dL [P < 0.0001]; 45 U/kg, 2.438 g/dL [95% CI, 1.488 to 3.389]), platelet counts (60 U/kg, 50.88 × 109/L [95% CI, 23.97 to 77.78]; 45 U/kg, 40.92 × 109/L [95% CI, 11.2 to 70.64]), spleen volumes (60 U/kg, −1.92% of body weight [95% CI, −3.04 to −0.79]; 45 U/kg, −1.87% of body weight [95% CI, −3.17 to −0.57]), and hepatic volumes (60 U/kg, −0.84% of body weight [95% CI, −1.58 to −0.11]). A subanalysis of the pediatric population showed clinical improvements at 12 months in both dosing groups: hemoglobin concentrations (60 U/kg, 1.74 g/dL [95% CI, 0.72 to 2.78]; 45 U/kg, 2.77 g/dL [95% CI, −0.99 to 6.53]), platelet counts (60 U/kg, 49.9 × 109/L [95% CI, −32.1 to 131.9]; 45 U/kg, 60.3 × 109/L [95% CI, −103.1 to 223.7]), spleen volumes (60 U/kg, −2.1 cm3 [95% CI, −5.3 to 1.1]; 45 U/kg, −0.7 cm3 [95% CI, −2.6 to 1.2]), and hepatic volumes (60 U/kg, −0.7 cm3 [95% CI, −1.4 to 0.0]; 45 U/kg, −0.3 cm3 [95% CI, −1.7 to 1.1]). Data comparing velaglucerase alfa with imiglucerase identified similar changes in hemoglobin concentrations at 1.624 g/dL and 1.488 g/dL, respectively, after 9 months of therapy. Safety was reported in 3 identified studies and in data reported from the early access program: 3 peer-reviewed publications, 3 studies reported in clinical trial registries, and 1 abstract publication. Patients experienced a minimal number of adverse effects, and most reactions were mild to moderate in severity; 1 patient developed an anaphylactoid reaction and was discontinued from the trial. Antibody formation has been described with velaglucerase alfa but when compared with that of imiglucerase, seroconversion is less frequent (1% and 23%, respectively). Dosing regimens, from 30 to 60 U/kg intravenously every other week, have been assessed. Currently, the manufacturer recommends 60 U/kg intravenously every other week; however, further studies and evaluation of current study dosing regimens are needed to determine if there is a lower effective dose. Conclusions: Although a minimal amount of data are available for this relatively new biological agent, velaglucerase alfa reportedly is effective in the achievement and maintenance of therapeutic goals in type 1 GD in both treatment-naive and patients previously treated with imiglucerase. This agent has been reasonably well tolerated in clinical trials and may be considered for use in symptomatic patients with type 1 GD.

Dasatinib: From Treatment of Imatinib-Resistant or -Intolerant Patients With Chronic Myeloid Leukemia to Treatment of Patients With Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Brian L. Abbott — 2012-01-30

Abstract: Background: Imatinib is an effective treatment for patients with newly diagnosed chronic phase chronic myeloid leukemia (CML-CP), but resistance to imatinib can occur. Second-generation BCR-ABL inhibitors have shorter onset times and higher rates of complete cytogenetic response (CCyR) than imatinib. Dasatinib has a half-maximal inhibitory concentration 325 times lower than imatinib for BCR-ABL substrate phosphorylation in vitro and is less susceptible to most known molecular mechanisms of BCR-ABL imatinib resistance. Objectives: This study summarized published data on the use of dasatinib in CML-CP, reviewed the importance of early response to therapy, and discussed additional therapies for patients with newly diagnosed disease. Methods: PubMed was searched through June 2011 for English-language publications with the following search terms: imatinib, dasatinib, nilotinib, chronic myeloid/myelogenous leukemia or CML, and clinical trial. To identify follow-up data from published trials and data on trials in progress and products in development, similar searches were conducted for abstract and clinical trial databases. Relevant articles and abstracts were identified as those reporting results of Phase II and III clinical trials, predictors of treatment response, and treatment guidelines. No prespecified inclusion or exclusion criteria were used. Results: Dasatinib was effective in patients resistant to imatinib and more effective than high-dose imatinib in patients with newly diagnosed CML who were resistant to standard dose imatinib. Compared with imatinib, dasatinib induced superior response rates and patient outcomes earlier in the disease. In a Phase III trial in patients with newly diagnosed CML-CP, dasatinib 100 mg once daily induced significantly higher and faster rates of confirmed CCyR and major molecular response by 12 months versus imatinib and was generally well tolerated. Early achievement of CCyR was associated with better long-term progression-free survival. Dasatinib was approved by the U.S. Food and Drug Administration and the European Medicines Agency for initial treatment of CML-CP. Conclusions: Dasatinib was an effective treatment with the potential to improve long-term outcomes for patients with newly diagnosed CML-CP.

A Network Meta-Analysis on the Efficacy of Serotonin Type 3 Receptor Antagonists Used in Adults During the First 24 Hours for Postoperative Nausea and Vomiting Prophylaxis

Derek H. Tang, Daniel C. Malone — 2012-02-02

Abstract: Background: The serotonin type 3 receptor antagonists (5-HT3 antagonists) ondansetron, granisetron, tropisetron, and dolasetron are potential prophylactic agents for patients with mild to moderate risk of postoperative nausea and vomiting (PONV). A few trials have been conducted to compare the efficacy among 2 to 3 of these 4 agents. However, the comparative efficacy of all four 5-HT3 antagonists has not yet been quantitatively investigated. Objective: The goal of this study was to investigate whether the 5-HT3 antagonists—ondansetron, granisetron, tropisetron, and dolasetron—differ in efficacy when used for the prevention of PONV. Methods: PubMed and the Cochrane Library were searched for randomized controlled, double-blind studies measuring efficacy in terms of PONV prophylaxis. A Bayesian meta-analysis was conducted using published studies of 5-HT3 antagonists for PONV prophylaxis. The odds of patients with no PONV and postoperative vomiting (POV) within each study arm 24 hours after surgery were the primary indices of drug efficacy. Data were extracted and analyzed via indirect comparisons using random effects Bayesian models in WinBUGS version 1.4.3. Results: A total of 85 studies were identified, representing 15,269 patients. The results indicate that granisetron was significantly better than ondansetron (odds ratio [OR] = 1.53 [95% credible interval (CI), 1.15–2.00]) and dolasetron (OR = 1.67 [95% CI, 1.12–2.38]) in preventing PONV. Four antiemetic drugs had comparable efficacy in terms of preventing POV: granisetron showed similar efficacy compared with ondansetron (OR = 1.49 [95% CI, 0.90–2.43]), tropisetron (OR = 1.69 [95% CI, 0.92–3.13]), and dolasetron (OR = 1.32 [95% CI, 0.71–2.38]). Ondansetron exhibited comparable efficacy compared with tropisetron (OR = 1.14 [95% CI, 0.66–1.96]) and dolasetron (OR = 0.88 [95% CI, 0.51–1.47]). Tropisetron and dolasetron were also similar in efficacy (OR = 0.78 [95% CI, 0.40–1.45]). All 5-HT3 antagonists were statistically significantly better at preventing PONV or POV than placebo. Conclusions: With respect to PONV prophylaxis, granisetron was significantly better than ondansetron and dolasetron; ondansetron, tropisetron, and dolasetron exhibited similar efficacy. With respect to POV prophylaxis, ondansetron, granisetron, tropisetron, and dolasetron seemed to have comparable efficacy.

A Meta-Analysis of the Effects of Interleukin-6 −174 G>C Genetic Polymorphism on Acute Graft-Versus-Host Disease Susceptibility

2012-02-03

Abstract: Background: The interleukin-6 (IL-6) −174 G>C genetic polymorphism has been implicated to play an important role in acute graft-versus-host disease (aGVHD). However, previous studies have yielded inconclusive results as to its role in patient susceptibility to aGVHD, and no study to date has systematically analyzed this polymorphism. Objective: A meta-analysis of the published evidence was conducted to estimate the true effect of the IL-6 −174 G>C genetic polymorphism in allogeneic hematopoietic stem cell transplantation (alloHSCT) patients and donors on the risk of aGVHD. Methods: Seven cohort studies, comprising 1287 recipient and donor pairs, were included after eliminating 62 studies that met the following exclusion criteria: irrelevant studies other than cohort studies, without sufficient data, and with overlapping data. Although interstudy heterogeneity existed, most studies were conducted in the United States or Europe and included adult patients with hematologic disease who received alloHSCT from human leukocyte antigen–matched or identical sibling donors. The effect of the polymorphism on aGVHD risk (grades I-IV, II-IV, and III-IV) was estimated from odds ratios with 95% confidence intervals for the dominant genetic model and recessive model, respectively. Results: Patients who received grafts from donors with the IL-6 G allele experienced more frequent grade I-IV aGVHD (odds ratio = 3.304 [95% confidence interval, 1.456-7.494]) and grade II-IV aGVHD (odds ratio = 1.738 [95% CI, 1.006 - 3.001]). Conclusions: To our knowledge, this is the first meta-analysis to evaluate the relation between a non–human leukocyte antigen gene polymorphism and the risk of aGVHD. Our meta-analysis combined the results of several studies and demonstrated that the donor IL-6 G allele is associated with an increased risk of grades I-IV and II-IV aGVHD.

Pharmacokinetic Comparison of 2 Formulations of Anastrozole (1 mg) in Healthy Korean Male Volunteers: A Randomized, Single-Dose, 2-Period, 2-Sequence, Crossover Study

2012-01-27

Abstract: Background: Anastrozole is an aromatase inhibitor used to treat advanced breast cancer in postmenopausal women. A generic 1-mg tablet of anastrozole was recently developed. Objective: The study was designed to provide data to submit to Korean regulatory authorities to allow marketing of the test formulation. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy male adult volunteers. Methods: This single-dose, randomized, double-blind, 2-way crossover trial was conducted in the Clinical Trial Center at the Asan Medical Center (Seoul, Korea). A total of 24 healthy male Korean volunteers were enrolled. Subjects were randomized to receive 1 mg of the test or reference formulation, and pharmacokinetic (PK) parameters were measured. After a 3-week washout period, the other formulation was administered, and PK parameters were measured again. Cmax and AUClast were determined from blood samples obtained at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, and 216 hours after drug administration. The formulations were considered bioequivalent if the 90% CIs of the geometric mean ratios of test-to-reference formulations for AUClast and Cmax were within the bioequivalence limits of 0.8 to 1.25. Nonlinear mixed-effect modeling and Monte Carlo simulations for both formulations were also conducted, and the results were used to characterize and compare the PK properties. Safety profile and tolerability were assessed using measurements of vital signs, clinical chemistry tests, and interviews. Results: All enrolled subjects completed the study. A total of 8 adverse events (AEs) were reported (2 on test formulation, 6 on reference formulation) in 7 of 24 participants. These AEs were headache (n = 1), hordeolum (n = 1), and abnormal laboratory test values (n = 6). Both formulations were well tolerated, and there were no serious AEs. Both formulations were best described by a 2-compartment disposition model with lag phase. The 90% CIs of the geometric mean ratios of test formulation to reference formulation were 0.96 to 1.08 for Cmax and 0.93 to 1.0 for AUClast. Conclusion: The test and reference formulations had similar PK parameters and similar plasma concentration-time profiles. The test formulation of anastrozole met the Korean regulatory criteria (AUC and Cmax) for assuming bioequivalence. ClinicalTrials.gov identifier: NCT01105299.

Efficacy and Safety of Additional 200-mg Dose of Celecoxib in Adult Patients With Postoperative Pain Following Extraction of Impacted Third Mandibular Molar: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase II Study in Japan

2012-01-30

Abstract: Background: Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought. Objective: Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests. Results: A total of 69 patients (celecoxib, 42/64 [65.6%]; placebo, 27/58 [46.6%]) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 [64.1%]) compared with the placebo group (15/58 [25.9%]) rated the study medication as “good” or “excellent” ≥2 hours after the additional dose (P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group (P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group (P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%). Conclusions: Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113.

Intra-anal Iferanserin 10 mg BID for Hemorrhoid Disease: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

Alexander Herold, John Dietrich, Roger Aitchison — 2012-01-13

Abstract: Background: Despite the prevalence of internal hemorrhoid disease (HD), there are few pharmacologic options. Iferanserin, a selective serotonin receptor antagonist, is being studied for use in the treatment of HD. Objective: This Phase IIb study evaluated the efficacy and tolerability of 10-mg twice-daily iferanserin intra-anal ointment for the cessation of bleeding and other symptoms associated with internal HD. Methods: This randomized, double-blind, placebo-controlled study was conducted at 5 sites in Germany. Outpatients with Goligher grade I, II, and/or III hemorrhoids and bleeding were randomly assigned to receive iferanserin ointment 10 mg or inactive vehicle (placebo) BID for 14 days. During treatment, patients rated the severity of HD symptoms daily on a 10-point scale using a diary form. At enrollment and study end, physicians recorded the frequency and intensity of HD symptoms, adverse events, and results from blood and urine analyses on clinical-report forms. Results: Of the 121 patients enrolled in the study, 118 were evaluable for tolerability and 111 for efficacy. The mean age of the tolerability population was 52.7 years, 78.9% were male, and all were white. The 2 groups had similar HD symptoms at baseline, but overall, patients in the placebo group had numerically higher grades of HD than did patients in the iferanserin group. Compared with placebo, iferanserin was associated with significantly lower patient-reported severity ratings of daily bleeding and itching, beginning at day 1 for bleeding and at day 2 for itching (P < 0.05), but not with reduced ratings for severity of other HD symptoms, including pain, tenderness, difficulty with defecation, fullness, throbbing, and gas. In the physician assessments, iferanserin was associated with significantly reduced bleeding frequency by day 14 compared with placebo (P < 0.05). Adverse events were mild and infrequent, with no significant differences in prevalences between the 2 treatment groups and no clinically significant changes in laboratory values in any patient. Conclusion: Compared with placebo, intra-anal iferanserin was associated with significantly reduced patient-reported severity of bleeding and itching and physician-assessed bleeding frequency in these patients presenting with grade I, II, and/or III internal hemorrhoids and bleeding at 5 sites in Germany. ClinicalTrials.gov identifier: 01483833.

Long-Term Persistence With the Immunomodulatory Drugs for Multiple Sclerosis: A Retrospective Database Study

2012-02-02

Abstract: Background: Immunomodulatory drugs (IMDs) for multiple sclerosis (MS) have been available in Canada since 1995 and are currently the most commonly prescribed treatment for MS. However, relatively little is known about the long-term persistence to these drugs. Objective: The purpose of this study was to describe patterns of, and factors associated with, long-term persistence to the first-line IMDs in an MS population in British Columbia, Canada. Methods: Study data were collected from the British Columbia MS database. Adults from British Columbia with definite MS who were prescribed a first-line IMD (interferon beta-1b, interferon beta-1a [subcutaneous and intramuscular], and glatiramer acetate) from January 1, 1995, through December 31, 2008, were eligible for the study. Time to discontinuation of use of all first-line IMDs (ie, switching among IMD therapies was allowed) and the initially prescribed IMD was assessed using Kaplan-Meier survival analysis and multivariate Cox regression. Results: A total of 1896 patients were included. Mean (SD) age was 40.2 (9.5) years, and 75.1% were female. Median time to discontinuation of all first-line IMD therapies was 6.3 years (95% CI, 5.8–6.7 years). Patients with a longer disease duration and higher level of disability were at higher risk for discontinuing use of the IMDs. Age, sex, and the initial IMD were not associated with discontinuation. Persistence appeared to have decreased over time (P = 0.01 for trend). Median time to discontinued use of, or switching from, the initially prescribed IMD was 2.9 years (95% CI, 2.5–3.2 years). Conclusions: Approximately half of the MS patients discontinued use of their IMD within 6 years. It is unknown whether this persistence is adequate because uncertainties remain regarding the optimal level of persistence to the IMDs. Further investigation is needed to examine why some individuals are more at risk for discontinuation of IMD therapy and why, in contrast to other chronic diseases, persistence to IMDs in patients with MS has not improved over time.

Evaluation of Gabapentin Enacarbil on Cardiac Repolarization: A Randomized, Double-Blind, Placebo- and Active-Controlled, Crossover Thorough QT/QTc Study in Healthy Adults

2012-02-01

Abstract: Background: Gabapentin enacarbil, a transported prodrug of gabapentin, was recently approved by the US Food and Drug Administration for the treatment of moderate to severe restless legs syndrome. Objective: As part of the overall safety evaluation of gabapentin enacarbil, the present definitive QT/QTc study was conducted to assess the effects of gabapentin enacarbil on cardiac repolarization in accordance with the International Conference on Harmonization E14 guidance. Methods: This randomized, double-blind, placebo- and active-controlled, crossover study enrolled 54 healthy adults. Subjects were randomly assigned to receive a single oral dose of gabapentin enacarbil 1200, 6000 mg, moxifloxacin 400 mg (active control), and placebo in a randomized sequence, with treatment periods separated by a 7-day washout. Blood samples were collected for pharmacokinetic analysis, and continuous ECG measurements were recorded using a Holter monitor. The primary end point was the time-matched difference in individualized baseline-adjusted QTc (ddQTcIb) between gabapentin enacarbil and placebo. General tolerability was also monitored. Results: Of the 54 subjects enrolled in the study (mean [SD] age, 29.2 [10.1]; 42.6% female; mean body mass index, 25.8 [3.0]), 48 (88.9%) completed the study, and 6 were discontinued prematurely after having received ≥1 dose of study medication. Thus, the numbers of patients in the safety population were: gabapentin enacarbil 1200 mg, 50; gabapentin enacarbil 6000 mg, 50; moxifloxacin, 50; and placebo, 51. The maximum ddQTcIb values were 0.7 msec (upper 95% confidence limit [CL], 3.0) with gabapentin enacarbil 1200 mg; 1.3 msec (upper CL, 3.6) with gabapentin enacarbil 6000 mg; and 7.4 msec (lower CL, 5.1) with moxifloxacin. A QT–concentration relationship was reported with moxifloxacin. Gabapentin exposures were dose-proportional with gabapentin enacarbil doses of 1200 and 6000 mg. The most commonly reported adverse events with gabapentin enacarbil 6000 mg were dizziness and somnolence (60.0% and 54.0%, respectively). Conclusion: In this population of healthy adults, gabapentin enacarbil at doses of 1200 and 6000 mg was not associated with QT prolongation and was generally well-tolerated.

Atomoxetine Treatment Outcomes in Adolescents and Young Adults With Attention-Deficit/Hyperactivity Disorder: Results From a Post Hoc, Pooled Analysis

2012-01-30

Abstract: Background: Many children with attention-deficit/hyperactivity disorder (ADHD) continue to experience this disorder as adults, which may, in part, be due to the discontinuity of health care that often occurs during the transition period between late adolescence and young adulthood. Although atomoxetine is reported to be efficacious in both adolescents and young adults, no longitudinal studies have been designed to assess directly the effects of atomoxetine treatment during this transition period. As a first step, we present the results of a post hoc, pooled analysis that compared the efficacy and safety profile of atomoxetine in these 2 patient populations. Objective: The aim of the present study was to assess the efficacy and safety profile of atomoxetine treatment in adolescents and young adults with ADHD. Methods: A post hoc, pooled analysis was conducted by combining data from 6 double-blind trials (6–9 weeks in duration) that studied adolescents (12–17 years of age; atomoxetine, n = 154; placebo, n = 88; mean final dose = 1.38 mg/kg) and 3 trials (10 weeks in duration) that studied young adults (18–30 years of age; atomoxetine, n = 117; placebo, n = 125; mean final dose = 1.21 mg/kg). Efficacy measures used in these analyses were ADHD Rating Scale (ADHDRS) for adolescents, Conners' Adult ADHD Rating Scale (CAARS) for young adults, and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) for both age groups. Treatment response was defined as ≥30% reduction from baseline in total ADHD symptom score. Results: In adolescents (mean age, 13.4 years), atomoxetine improved ADHD significantly compared with placebo (ADHDRS total score change, −12.9 vs −7.5; P < 0.001). In young adults (mean age, 24.7 years), atomoxetine improved ADHD significantly (CAARS total score change, −13.6 vs −7.7; P < 0.001; CGI-ADHD-S change, −1.1 vs −0.6; P < 0.001). No significant treatment-by-age subgroup interaction was observed. Tolerability was similar for both age subgroups, except for treatment-emergent nausea, which occurred significantly more frequently with atomoxetine than with placebo in young adults (13.7% vs 4.8%, respectively; P = 0.024); in adolescents no statistically significant differences were observed in frequency of nausea between atomoxetine and placebo treatment (4.5% vs 10.2%, respectively; P = 0.108). Conclusions: Results from this post hoc, pooled analysis suggest that acute treatment with atomoxetine was efficacious in both adolescent and young adult patients with ADHD. The safety profile findings from this study were consistent with the previously reported atomoxetine safety and tolerability profiles, suggesting that it may be continued during the transition from adolescence to young adulthood.

Effect of Statins on Total Cholesterol Concentrations, Cardiovascular Morbidity, and All-Cause Mortality in Chronic Obstructive Pulmonary Disease: A Population-Based Cohort Study

2012-01-16

Abstract: Background: The benefit of statin use on total cholesterol (TC) concentration has not been studied previously in patients with chronic obstructive pulmonary disease (COPD). Objective: Our study aimed to evaluate statin-associated TC-concentration reduction and subsequent risk for cardiovascular (CV) morbidity and mortality in COPD. Methods: We performed a population-based cohort study using a record-linkage database in Tayside, Scotland. A total of 1017 COPD patients who had at least 2 separate TC measurements between 1993 and 2007 were studied. They were categorized into statin-exposed and statin-unexposed groups according to their statin use status during follow-up. Main outcomes were TC-concentration change from baseline, CV events, and all-cause mortality during follow-up. Multivariate Cox regression models with a time-dependent variable for statins were used to assess risk for outcomes. Results: Statin-associated TC concentrations decreased by 0.86 mmol/L (16%) in patients treated for primary prevention (PP) (n = 1274) and 0.52 mmol/L (11%) in patients treated for secondary prevention (SP) (n = 443), from 5.30 mmol/L and 4.68 mmol/L at baseline, respectively. TC concentrations also declined by 2% in patients free from established CV disease and by 5% in patients with established CV disease in the statin-unexposed groups. A risk reduction of recurrent CV events with statins was observed (adjusted hazard ratio [HR] = 0.35; 95% CI, 0.15−0.87), but not for PP (adjusted HR = 0.84; 95% CI, 0.37−1.89). Statins reduced CV mortality (adjusted HR = 0.32; 95% CI, 0.13−0.77) in SP but not PP. There were statistically significant reductions in all-cause mortality in both PP (adjusted HR = 0.61; 95% CI, 0.43−0.85) and SP (adjusted HR = 0.58; 95% CI, 0.35−0.97). Conclusions: In patients with COPD, statins were protective from CV events and CV mortality in SP but not PP, and statins improved all-cause mortality in both PP and SP.

Two Decades of Experience With the Haemophilus influenzae Serotype b Conjugate Vaccine in the United Kingdom

Shamez N. Ladhani — 2012-01-16

Abstract: Background: The Haemophilus influenzae serotype b (Hib) conjugate vaccine was introduced into the UK national childhood immunization program in 1992 after clinical trials reported the vaccine to be highly immunogenic in infants as young as two months of age. Objective: The goal of this study was to describe and comment on the impact of routine Hib immunization on the epidemiology of invasive Hib disease in the United Kingdom. In addition, the development of Hib polysaccharide and conjugate vaccines was reviewed. Methods: A literature search was conducted of PubMed for invasive Hib disease epidemiology in the United Kingdom. The UK Health Protection Agency Web site was also searched for relevant publications. Results: The incidence of invasive Hib incidence in children aged <5 years fell from 21/100,000 to 44/100,000 in the prevaccine era to 0.63/100,000 in 1998, with an estimated vaccine failure rate of 2.2/100,000 vaccinees. After 1999, however, invasive Hib disease increased, particularly in toddlers, and peaked in 2003. Potential reasons for the resurgence included a greater-than-expected decline in Hib antibodies after primary immunization, waning of herd immunity offered by the initial catch-up campaign, and use of a less immunogenic Hib combination vaccine containing acellular pertussis in 2000–2001. In response to the resurgence, a Hib combination vaccine containing whole-cell pertussis was reintroduced in 2002, followed by a childhood Hib booster campaign in 2003. In 2004, the recommended infant vaccine was changed to a different Hib/acellular pertussis combination vaccine containing inactivated polio, which had a satisfactory Hib response, was less reactogenic, and eliminated the risk of vaccine-associated paralytic poliomyelitis. This action was followed by introduction of a routine 12-month Hib booster in 2006. Together, these measures led to a decline in invasive Hib disease across all age groups. In 2010, there were only 30 invasive Hib cases, with 6 reported in children aged <5 years and no deaths in this age group since 2007. Conclusions: Control of Hib disease is currently the best that has been achieved since the introduction of the routine Hib vaccination almost 20 years ago.

Biosimilars: Impact of Biologic Product Life Cycle and European Experience on the Regulatory Trajectory in the United States

Islah Ahmed, Ben Kaspar, Uma Sharma — 2012-01-16

Abstract: Background: Biosimilars are defined as biologic products that are highly similar to reference products, notwithstanding minor differences in clinically inactive components, with no clinically meaningful differences between the biologic product and the reference product in terms of safety profile, purity, and potency. Due to the high cost of innovator biologics, as well as an increase in the number of these products reaching patent expiry, the development of a process for approving biosimilar products has become a crucial regulatory issue in the United States. Objective: This commentary explores the relationship between structural/biophysical variation and the risk/benefit profile of biosimilars and reference biologics that have undergone process changes in the context of the most recent biophysical, nonclinical, and clinical data available. Methods: The search strategy used PubMed, EMBASE, and MEDLINE for the retrieval of documents pertaining to biologic manufacturing, comparative analysis of biosimilars and originator biologics, and relevant review articles on biosimilars. For regulatory documents pertaining to the processes of the approval of biosimilars, biologics, and generics, a search for legislative decisions, briefing summaries, concept papers, guidance, and evaluations of approved and rejected applications for biosimilars published by the World Health Organization, US Food and Drug Administration, European Medicines Agency (EMA), and other national regulatory authorities was conducted. Selected articles from key opinion leaders and manufacturers were also reviewed. These searches were conducted to provide a review of historical and contemporary issues in the consideration of the current status of worldwide biosimilar use and regulation. Results: A total of 18 marketing applications covering 9 development programs were surveyed. Of these, 14 applications were approved and 4 were rejected by the EMA. None of the biosimilars were reported to have evidence of significant clinical variation relative to reference compounds in the absence of corresponding differences in biophysical properties. A single biosimilar (Omnitrope® [somatropin]) was reported to have evidence of significant variation in both biophysical and clinical parameters in premarketing studies. Biophysical variation in the absence of relevant differences in the efficacy and safety profiles compared with the reference brands was noted for 2 biosimilar epoetin products. Conclusions: This commentary provides evidence that current EU guidelines have resulted in the approval of biosimilar therapeutics with comparable efficacy and safety profiles for the recommended indications of their respective reference originator biologics. It is anticipated that these precedents will serve as a starting point in the development of a process for approving biosimilars in the United States and worldwide to provide efficacious and tolerable biotherapeutics with a significant cost advantage for national health care programs and consumers.

Metabolism, Excretion, and Pharmacokinetics of [14C]-Radiolabeled Aleglitazar: A Phase I, Nonrandomized, Open-Label, Single-Center, Single-Dose Study in Healthy Male Volunteers

2012-01-16

Abstract: Background: Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist with a balanced activity (similar half-maximal effective concentrations) toward PPAR-α and -γ that is in clinical development for the treatment of patients who have experienced an acute coronary syndrome and have type 2 diabetes mellitus. Objective: This study aimed to characterize the metabolic profile and the routes and rates of elimination of aleglitazar and its major metabolites in humans. Methods: In this Phase I, nonrandomized, open-label, single-center, single-dose study, 6 healthy male subjects each received a single oral dose of 300 μg [14C]-labeled aleglitazar. Total urine and feces were collected for up to 15 days. Venous blood samples were collected to determine the plasma concentrations of aleglitazar and its metabolites and for radioactivity counting. Results: The median age (range) and mean (SD) body mass index of subjects were 48 (41–60) years and 24.8 (3.0) kg/m2, respectively. Recovery of total radioactivity, as a percentage of the dose administered, was high (93 [3]%). Aleglitazar was predominantly eliminated in feces (mean, 66% [range, 55%–74%]), with only 28% (range, 22%–36%) of the radioactivity recovered in urine. Only a mean (SD) of 1.8 (0.8)% of aleglitazar was eliminated unchanged as parent compound in feces and only 0.3 (0.4)% was eliminated in urine. Almost all excreted drug-related material could be attributed to its 2 main metabolites, M1 (21%) and M6 (38%). Treatment with aleglitazar was well tolerated, and no serious adverse events were reported. Conclusions: In healthy volunteers, aleglitazar was excreted mainly in the form of inactive metabolites, mostly M1 and M6, with only a small proportion eliminated unchanged.

Price and Value: The Pharmacoeconomics of Scarcity

Alan Lyles — 2012-02-01

Pharmaceutical shortages threaten clinical care outcomes and third-party payer, government, and personal finances, yet these shortages are not routinely considered in pharmacoeconomic analyses.

Efficacy of Bypassing Agents in Patients With Hemophilia and Inhibitors: A Systematic Review and Meta-Analysis

Zheng-Yi Zhou, Joel W. Hay — 2012-01-30

Abstract: Background: Activated prothrombin complex concentrate (aPCC) and recombinant Factor VIIa (rFVIIa) are 2 bypassing agents commonly used for treating acute bleeds in hemophiliac patients with inhibitors. A wide range of efficacy rates for aPCC and rFVIIa have been reported in a number of single-armed and randomized controlled comparative studies. Objective: The aims of this study were to compare the clinical efficacy of aPCC and rFVIIa using a classic meta-analytic approach and to explore the role of study characteristics as covariates in a meta-analysis of previously published clinical studies in hemophiliac patients with antibodies to the missing Factor VIII or IX. Methods: A systematic search was conducted to identify studies on the efficacy of aPCC and rFVIIa 90 and 270 μg/kg for treating joint bleeds. The efficacy rates with aPCC and rFVIIa were pooled separately, assuming fixed or random effects. Subgroup analyses were conducted to pool the efficacy rates for bleeds evaluated at 8–12, 18–27, and 36–72 hours after the start of the initial infusion. Meta-regression was used to investigate the association between pooled efficacy rates and study characteristics. Results: Although only 2 studies directly compared the efficacy of aPCC and rFVIIa, data from ∼2392 joint bleeding episodes from 19 studies were included. The pooled efficacy rates were 80.8% with aPCC and 68.4% with rFVIIa (90 μg/kg, 72.0%; 270 μg/kg, 55.7%). The pooled efficacy rates with aPCC at 8–12, 18–27, and 36–72 hours were 49.2%, 70.2%, and 90.9%, respectively. The corresponding pooled rates with rFVIIa 90 μg/kg were 66.6%, 70.7%, and 77.7%. No significant differences were found between the pooled efficacy rates with aPCC and rFVIIa overall or at any of the time points evaluated. Positive associations were found between reported efficacy and duration of follow-up and the number of bleeds evaluated. Conclusions: Given the paucity of high-quality studies, the findings from the present review and meta-analysis suggest no conclusive evidence that aPCC or rFVIIa is significantly more efficacious than the other in the treatment of joint bleeding episodes in hemophiliac patients with inhibitors.

Cost-Effectiveness Analysis of Ranibizumab versus Verteporfin Photodynamic Therapy, Pegaptanib Sodium, and Best Supportive Care for the Treatment of Age-Related Macular Degeneration in Greece

2012-01-30

Abstract: Background: Age-related macular degeneration (AMD) is a progressive disease that results in loss of central vision, significant functional impairment, and a subsequent heavy socioeconomic burden. AMD treatments delay disease progression, improve patient outcomes, and reduce resource use associated with visual impairment, however, in a varying way concerning costs and effects. Objective: The purpose of this study was to investigate the cost effectiveness of ranibizumab compared with verteporfin photodynamic therapy, pegaptanib sodium, and best supportive care for the treatment of AMD in Greece. Methods: A 6-state Markov model was constructed according to patient visual acuity in the better-seeing eye. Data on effectiveness were derived from randomized controlled trials evaluating the outcomes of ranibizumab versus alternative AMD treatments. Resource utilization reflected the Greek health care setting and was defined by a panel of experts. All treatments were administered for a 2-year period and evaluated during a 10-year time frame from a third-party payer perspective and discounted at 3.5% per annum. Results: Estimated mean 10-year direct costs of treatment in the ranibizumab arm ranged from €23,733 to €31,795 (2011 Euros), with a projected gain of 4.50 to 4.74 quality-adjusted life years (QALYs) or 2.97 to 4.47 vision years, depending on type of lesion. For predominantly classic lesions, the cost per QALY gained with ranibizumab was estimated at €6444/QALY (95% uncertainty interval [UI], €−30,403/QALY to €44,524/QALY), €15,344 (95% UI, €−11,433 to €53,554) and dominant relative to photodynamic therapy, best supportive care, and pegaptanib, respectively. Corresponding ratios for patients with minimally classic lesions were €24,580/QALY (95% UI, €−5580/QALY to €76,229/QALY) and €13,112/QALY (95% UI, €−3839/QALY to €37,527/QALY) for ranibizumab relative to best supportive care and pegaptanib, and for patients with occult lesions were estimated at €19,407/QALY (95% UI, €−1486 to €46,434) and €28,561/QALY (95% UI, €6143 to 73,431), respectively. Sensitivity analysis provided robust results in all cases. Conclusion: Ranibizumab can be a cost-effective option for the treatment of AMD compared with selected alternatives in the Greek health care setting.

Factors Associated With the Initiation of Disease-Modifying Antirheumatic Drugs in Newly Diagnosed Rheumatoid Arthritis: A Retrospective Claims Database Study

2012-01-30

Abstract: Objectives: The objectives of this study were to quantify the proportion of US patients with newly diagnosed rheumatoid arthritis (RA) in whom disease-modifying antirheumatic drug (DMARD) therapy was initiated within 12 months following diagnosis, to determine mean time to initiation, to compare the characteristics of initiators versus noninitiators, and to identify factors associated with noninitiation. Methods: A retrospective study was conducted using claims from the databases of commercial managed care and Medicare supplemental managed care to identify patients with claims containing codes for RA dated January 1, 2004, through September 30, 2008. The percentage of patients with RA and a prescription for a DMARD within 12 months after the index date (initiators) was evaluated. The characteristics of DMARD initiators and noninitiators during the preindex period were compared, including demographic and clinical characteristics, health care resource utilization, and cost variables. The probability of DMARD initiation was determined using survival analysis. Multivariate analysis was performed to estimate mean time from diagnosis to DMARD initiation based on demographic and clinical variables. Results: Of 26,911 patients with newly diagnosed RA identified in the database searches, 63% had been prescribed a DMARD within 12 months after diagnosis. DMARD initiators were significantly more likely to have had a rheumatologist visit and rheumatoid factor testing and were more likely to have received a corticosteroid and/or an NSAID (all, P < 0.001). DMARD initiators had significantly lower total costs ($10,534 vs $12,725, respectively) and pharmacy drug costs ($2438 vs $2822) over the preindex period compared with noninitiators (both, P < 0.001). Independent factors associated with a greater likelihood of DMARD initiation included a rheumatologist visit, rheumatoid factor testing, NSAID use, and corticosteroid use. Age ≥85 years and the presence of comorbidities were associated with a significantly lower likelihood of DMARD initiation. Conclusions: Among managed care enrollees in the present analysis, 37% of patients newly diagnosed with RA were not being treated with DMARDs in the first 12 months after diagnosis. Time to DMARD initiation plateaued after 90 days, suggesting that if a patient was not prescribed a DMARD soon after RA diagnosis, he or she was not likely to receive one.

Costs of Trastuzumab in Combination With Chemotherapy for HER2-Positive Advanced Gastric or Gastroesophageal Junction Cancer: An Economic Evaluation in the Chinese Context

Bin Wu, Ming Ye, Huafeng Chen, Jinfang F. Shen — 2012-02-01

Abstract: Background: Adding trastuzumab to a conventional regimen of chemotherapy can improve survival in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (GEJ) cancer, but the economic impact of this practice is unknown. Objective: The purpose of this cost-effectiveness analysis was to estimate the effects of adding trastuzumab to standard chemotherapy in patients with HER2-positive advanced gastric or GEJ cancer on health and economic outcomes in China. Methods: A Markov model was developed to simulate the clinical course of typical patients with HER2-positive advanced gastric or GEJ cancer. Five-year quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) were estimated. Model inputs were derived from the published literature and government sources. Direct costs were estimated from the perspective of Chinese society. One-way and probabilistic sensitivity analyses were conducted. Results: On baseline analysis, the addition of trastuzumab increased cost and QALY by $56,004.30 (year-2010 US $) and 0.18, respectively, relative to conventional chemotherapy, resulting in an ICER of $251,667.10/QALY gained. Probabilistic sensitivity analyses supported that the addition of trastuzumab was not cost-effective. Budgetary impact analysis estimated that the annual increase in fiscal expenditures would be ∼$1 billion. On univariate sensitivity analysis, the median overall survival time for conventional chemotherapy was the most influential factor with respect to the robustness of the model. Conclusions: The findings from the present analysis suggest that the addition of trastuzumab to conventional chemotherapy might not be cost-effective in patients with HER2-positive advanced gastric or GEJ cancer.

Tolerability and Pharmacokinetics of a New P-Glycoprotein Inhibitor, HM30181, in Healthy Korean Male Volunteers: Single- and Multiple-Dose Randomized, Placebo-Controlled Studies

2012-01-30

Abstract: Background: HM30181 is an oral P-glycoprotein (P-gp) inhibitor developed to enhance the oral bioavailability of P-gp substrate drugs. Objective: The objective of this study was to investigate the tolerability and pharmacokinetic properties of HM30181 after single and multiple oral administrations to healthy Korean male volunteers. The study was performed to meet regulatory criteria for marketing the test product in South Korea. Methods: A dose-block–randomized, double-blind, placebo-controlled, dose-escalation study was performed in 180-, 360-, 600-, and 900-mg single-dose groups and 60-, 180-, and 360-mg multiple-dose groups with 10 subjects (8 active; 2 placebo) per group. In the single-dose study, blood and urine samples were collected for up to 120 hours after drug administration. In the multiple-dose study, subjects received the study drug or placebo orally once daily for 5 days. Blood samples were collected up to 624 hours after the last dose, and up to 24 hours after the first dose to evaluate the accumulation index. Urine samples were collected up to 120 hours after the last dose. Pharmacokinetic analysis was performed using noncompartmental methods. Adverse events were collected by the spontaneous reporting of the subjects or when subjects were asked general health-related questions. Results: Thirty and 70 healthy male volunteers completed the single- and multiple-dose studies, respectively. Mean (SD) age and body weight of subjects in the single administration group were 24.0 (1.8) years and 68.8 (7.4) kg, respectively, and those of the multiple administration group were 24.5 (2.6) years and 67.6 (7.7) kg, respectively. The plasma concentrations peaked at 14 to 42 hours and declined with t½ of 75.7 to 169.3 hours after single administration, and peaked at 5.5 to 8.0 hours and declined with t½ of 153.5 to 215.2 hours after multiple administrations. Cmax and area under the concentration curve within dosing intervals (AUCτ) increased dose dependently after single administration; however, dose-dependent increases in Cmax and AUCτ were not observed after multiple administrations. The fraction of drug excreted unchanged in urine was minimal, with values <0.01% in all dose groups. HM30181 accumulated after multiple administrations with an accumulation index of 4.0 to 7.4. All adverse events reported were mild in intensity; there were no serious adverse events reported. The most frequently reported adverse event was gastrointestinal disorder. Conclusions: HM30181 was well tolerated after oral administration within the dose range evaluated, with the exception of the repeated administration of 360 mg, for which gastrointestinal disorders were frequently reported. The systemic exposure of HM30181 was relatively low, and dose proportional properties of HM30181 were not observed.

Pharmacokinetics and Safety Profile of Tigecycline in Children Aged 8 to 11 Years With Selected Serious Infections: A Multicenter, Open-Label, Ascending-Dose Study

2012-01-16

Abstract: Background: Tigecycline, a broad-spectrum antibiotic used for treating serious bacterial infections in adults, may be suitable for pediatric use once an appropriate dosage is determined. Objective: The aim of this study was to assess the pharmacokinetic (PK) properties, safety profile, and descriptive efficacy of tigecycline. Methods: In this Phase II, multicenter, open-label clinical trial, children aged 8 to 11 years with community-acquired pneumonia (CAP), complicated intra-abdominal infection (cIAI), or complicated skin and skin structure infections (cSSSI) were administered tigecycline 0.75, 1, or 1.25 mg/kg. Results: A total of 58 patients received ≥1 dose of tigecycline (31 boys; 44 white; mean age, 10 years; mean weight, 35 kg); 47 had data from samples available for PK analysis. The mean (SD) PK values were: Cmax, 1899 (2954) ng/mL; Tmax, 0.56 (0.18) hour; between-dose AUC, 2833 (1557) ng · h/mL; weight-normalized clearance, 0.503 (0.293) L/h/kg; and Vdss, 4.88 (4.84) L/kg. Overall clinical cure rates at test-of-cure were 94% (16/17), 76% (16/21), and 75% (15/20) in the 0.75-, 1-, and 1.25-mg/kg cohorts, respectively. The rates of protocol violations were higher in the 1- and 1.25-mg/kg groups, resulting in higher proportions of indeterminate clinical cure assessments relative to the 0.75-mg/kg cohort (19% and 15% vs 0%). The most frequent adverse event was nausea, which occurred in 50% of patients overall (29/58) and the prevalence of which was significantly higher in the 1.25-mg/kg group versus the 0.75-mg/kg group (65% vs 18%; P = 0.007). Pharmacodynamic simulations using MIC data from an ongoing microbiological surveillance trial predicted that a dosage of 1.2 mg/kg q12h would lead to therapeutic target attainment levels of up to 82% for the target AUC0–24/MIC ratios. Conclusion: A tigecycline dosage of ∼1.2 mg/kg q12h may represent the most appropriate dosage for subsequent evaluation in Phase III clinical trials in children aged 8 to 11 years with selected serious bacterial infections. ClinicalTrials.gov identifier: NCT00488345.

Correction

2012-01-20

In the article “Incidence of Cardiovascular Events in Which 2 Thiazolidinediones Are Used as Add-on Treatments for Type 2 Diabetes Mellitus in a Taiwanese Population” (Clin Ther. 2011;33:1904–1913), the order of authors has changed. The original order of authors was Chin-Chieh Chou; Wei-Liang Chen; Tung-Wei Kao; Yaw-Wen Chang; Ching-Hui Loh; and Chung-Ching Wang. The correct order of authors is as follows: Chung-Ching Wang; Wei-Liang Chen; Tung-Wei Kao; Yaw-Wen Chang; Ching-Hui Loh; and Chin-Chieh Chou.