Abstract
Pharmacokinetics (PKs) in Japanese healthy subjects were simulated for nine compounds using physiologically based PK (PBPK) models parameterized with physicochemical properties, preclinical absorption, distribution, metabolism, and excretion (ADME) data, and clinical PK data from non-Japanese subjects. For each dosing regimen, 100 virtual trials were simulated and predicted/observed ratios for peak plasma concentration (C(max) ) and area under the curve (AUC) were calculated. As qualification criteria, it was prespecified that >80% of simulated trials should demonstrate ratios to observed data ranging from 0.5-2.0. Across all compounds and dose regimens studied, 93% of simulated C(max) values in Japanese subjects fulfilled the criteria. Similarly, for AUC, 77% of single-dosing regimens and 100% of multiple-dosing regimens fulfilled the criteria. In summary, mechanistically incorporating the appropriate ADME properties into PBPK models, followed by qualification using non-Japanese clinical data, can predict PKs in the Japanese population and lead to efficient trial design and conduct of Japanese phase I studies.