A post hoc analysis of intra-subject coefficients of variation in pharmacokinetic measures to calculate optimal sample sizes for bioequivalence studies

Abstract

Because bioequivalence studies are performed using a crossover design, information on the intrasubject coefficient of variation (intra-CV) for pharmacokinetic measures is needed when determining the sample size. However, calculated intra-CVs based on bioequivalence results of identical generic drugs produce different estimates. In this study, we collected bioequivalence results using public resources from the Ministry of Food and Drug Safety (MFDS) and calculated the intraCVs of various generics. For the generics with multiple bioequivalence results, pooled intra-CVs were calculated. The estimated intra-CVs of 142 bioequivalence studies were 14.7±8.2% for AUC and 21.7±8.8% for C max . Intra-CVs of C max were larger than those of area under the concentrationtime curve (AUC) in 129 studies (90.8%). For the 26 generics with multiple bioequivalence results, the coefficients of variation of intra-CVs between identical generics (mean±sd (min ~ max)) were 38.0±24.4% (1.9 ~ 105.3%) for AUC and 27.9±18.2% (4.0 ~ 70.1%) for C max . These results suggest that substantial variation exists among the bioequivalence results of identical generics. In this study, we presented the intra-CVs of various generics with their pooled intra-CVs. The estimated intraCVs calculated in this study will provide useful information for planning future bioequivalence studies. (This is republication of the article 'Transl Clin Pharmacol 2017;25:179-182

Current Bioequivalence Study Designs in South Korea: A Comprehensive Analysis of Bioequivalence Study Reports Between 2013 and 2019

“…Margin of error on a log scale was calculated as the difference of the natural logarithm of PE and the lower limit of the CI [Δ ln(PE) − ln(CI lower )]. Mean squared error (MSE) and intrasubject CV were calculated using the following equations (Chung et al, 2018):…”

“…The second step was the pooling and conversion of the estimated intrasubject CVs to the corresponding sample sizes. The intrasubject CV was pooled for drugs with a different formulation or fasting status (e.g., metformin hydrochloride, metformin hydrochloride ER, and metformin hydrochloride ER (fed) were calculated separately) using a method described previously (Chung et al, 2018). Estimation of the sample sizes was performed with the following criteria: R version 3.6.3.…”

“…Margin of error on a log scale was calculated as the difference of the natural logarithm of PE and the lower limit of the CI . Mean squared error (MSE) and intrasubject CV were calculated using the following equations ( Chung et al, 2018 ): ( t : t-values of the student t-distribution, α: probability of type I error (assumed 0.05), , : sample sizes of each group).…”

“…The second step was the pooling and conversion of the estimated intrasubject CVs to the corresponding sample sizes. The intrasubject CV was pooled for drugs with a different formulation or fasting status (e.g., metformin hydrochloride, metformin hydrochloride ER, and metformin hydrochloride ER (fed) were calculated separately) using a method described previously ( Chung et al, 2018 ). Estimation of the sample sizes was performed with the following criteria: • Significance level ( α ): 0.05 • Power (1 − β ): 80 and 90% (calculated separately) • Treatment to reference ratio: 1.05 (based on the convention) ( Ring et al, 2019 ) • Intrasubject CV: maximum of pooled intrasubject CV of C max or AUC last …”

Pharmacokinetic Comparison Between a Fixed-Dose Combination of Atorvastatin/Omega-3-Acid Ethyl Esters and the Corresponding Loose Combination in Healthy Korean Male Subjects

“…A replicated crossover design was applied owing to the highly variable characteristics of atorvastatin and omega-3 fatty acids. 15 , 16 Subjects were randomly assigned to one of the 2 sequences ( Figure 1 ) and received FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg × 4) or a loose combination of atorvastatin tablets (Lipitor, Pfizer Ltd., 10 mg × 4) and omega-3-acid ethyl ester soft capsules (Omacor, Kuhnil Pharmaceutical, Co. Ltd., 1000 mg × 4) with a high-fat meal (≥900 kcal and ≥35% lipid content) in each period. The study dose was selected to evaluate the pharmacokinetics of atorvastatin and omega-3 fatty acids at the highest approved dosage.…”