Genotype-based enrichment study design for minimizing the sample size in bioequivalence studies using tolterodine and CYP2D6 genotype .

Abstract

The objective of this study was to explore a pharmacogenomic information-based enrichment study design for reducing the sample size in bioequivalence (BE) studies using tolterodine and CYP2D6 genotypes. A BE study of tolterodine was performed in a randomized, open-label, 2×2 cross-over design. A two one-sided test (TOST) was executed for pharmacokinetic (PK) parameters of tolterodine, and their geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were estimated. The coefficient of variation (CV) was calculated for each cytochrome P450 (CYP) 2D6 genotype group, and the sample size required to meet the power of an equivalence test was estimated, based on TOST in genotype stratified groups as well as in a conventional group. Replicated simulation datasets of PK parameters for each genotype group were generated using bootstrap resampling technique. The CVs of PK parameters in the conventional dataset were much greater than those in the genotype-based stratified groups. While up to 70 subjects were required for statistical power based on the CV of the area under the concentration-time curve (AUCt) observed in the conventional dataset, only 26 - 44 subjects in extensive metabolizers (EMs) and poor metabolizers (PMs), respectively, were required for the CYP2D6 genotype groups. The 90% CIs for GMR in all simulated datasets appeared to meet the BE criterion (0.8-1.25). This exploration demonstrated that a drug-metabolizing enzyme genotype-based enrichment strategy can be implemented to minimize the sample size in BE studies of drugs that have high PK variability due to polymorphic metabolizing enzyme(s).