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

Because bioequivalence studies are performed using a crossover design, information on the intra-subject 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 intra-CVs 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 Cmax. Intra-CVs of Cmax were larger than those of area under the concentration-time 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 Cmax. 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 intra-CVs 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' retracted from critical typographic errors. See the 'Retraction and Republication section of this issue for further information)

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

The retraction has been agreed upon due to critical typographical errors throughout the contents from accidents at the manuscript editing step.

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

Because bioequivalence studies are performed using a crossover design, information on the intra-subject 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 intra-CVs 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 concentration-time 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 intra-CVs calculated in this study will provide useful information for planning future bioequivalence studies.

A bioequivalence study of two levofloxacin tablets in healthy male subjects

Levofloxacin is a bactericidal broad spectrum antibiotic against Gram-positive and Gram-negative pathogens. A randomized, two-treatment, two-period, two-way crossover study was conducted to evaluate the bioequivalence of Lectacin 250 mg tablet, a generic levofloxacin, to its reference drug, Cravit 250 mg tablet. Each period was separated by a 7-day washout. Serial blood samples were collected until 24 h after dosing and plasma levofloxacin concentrations were determined using a high performance liquid chromatography. Pharmacokinetic parameters were analyzed using K-BE Test 2007 and BA calc 2007 (Ministry of Food and Drug Safety, Cheongju-si, South Korea). The peak concentration (Cmax) and the area under the plasma concentration versus time curve from 0 to the last measurable concentration (AUC(0-t)) for the generic and reference levofloxacin were 4.48+/-0.89 mg/L and 4.46+/- 0.95 mg/L, and 25.33+/-4.12 mg*h/L and 25.77+/-4.01 mg*h/L, respectively, leading to a geometric mean ratio (90% confidence interval) of the generic to the reference levofloxacin of 1.0060 (0.9339-1.0842) and 0.9810 (0.9476-1.0159), respectively, for Cmax and AUC(0-t). Lectacin 250 mg tablet is bioequivalent to Cravit 250 mg tablet.