Abstract
Ethnic differences in the oral clearance of drugs are an important issue for pharmaceutical industries and regulatory agencies because of the potential need for dose adjustment in each country. The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has required pharmaceutical industries to conduct Phase I clinical trials in Japanese subjects for several decades, therefore many comparative data are existed on pharmacokinetics between Japanese and Westerners. A serious concern regarding the assessment of ethnic differences is the validity of comparisons between clinical trials conducted under different conditions, i.e. inter-study variability (ISV).
In this study, the ethnic ratios (ERs) of oral clearance between Japanese and Western populations were subjected to a model-based meta-analysis (MBMA) of 81 drugs evaluated in 673 clinical trials. Drugs were classified into 8 groups according to clearance mechanism, and ERs for each group were modeled in a hierarchical structure with the relationship between inter-individual variability (IIV), ISV, and intra-group variability between drugs (IDV), and were estimated simultaneously using Markov chain Monte Carlo (MCMC) methods.
ER, IIV, ISV, and IDV were dependent on clearance mechanism, and ethnic differences were generally small, except for some groups such as drugs metabolized by polymorphic enzymes or drugs for which no clearance mechanism could be identified. Group trends in IIV were well matched across ethnicities, and ISV was about half that of IIV as a coefficient of variation. It suggests that a methodology that assumes a mechanism for ethnic differences in pharmacokinetics, classifies drugs based on this mechanism, and uses statistical methods to perform MBMA can provide a rational understanding of ethnic differences and aid in strategic drug development.
