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Pharmacokinetics (PK) in Japanese healthy subjects were simulated for nine compounds using physiologically based pharmacokinetic (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 C and AUC were calculated. As qualification criteria, it was pre-specified that over 80% of simulated trials should demonstrate ratios to observed data ranging from 0.5 to 2.0. Across all compounds and dose regimens studied 93% of simulated C 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 PK in Japanese population and lead to efficient trial design and conduct of Japanese Phase I studies. This article is protected by copyright. All rights reserved.
This article was published in the following journal.
Name: Clinical pharmacology and therapeutics
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