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Drug Metab Pharmacokinet. 2017 Dec;32(6):277-285. doi: 10.1016/j.dmpk.2017.09.001. Epub 2017 Sep 15.

Prediction of inter-individual variability on the pharmacokinetics of CYP2C8 substrates in human.

Author information

1
Chugai Pharmabody Research Pte. Ltd., Singapore. Electronic address: haraya.kenta@chugai-pharm.co.jp.
2
Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
3
Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Yokohama, Japan; Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Japan.
4
Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Japan.

Abstract

Inter-individual variability in pharmacokinetics can lead to unexpected side effects and treatment failure, and is therefore an important factor in drug development. CYP2C8 is a major drug-metabolizing enzyme known to be involved in the metabolism of over 100 drugs. In this study, we predicted the inter-individual variability in AUC/Dose of CYP2C8 substrates in healthy volunteers using the Monte Carlo simulation. Inter-individual variability in the hepatic intrinsic clearance of CYP2C8 substrates (CLint,h,2C8) was estimated from the inter-individual variability in pharmacokinetics of pioglitazone, which is a major CYP2C8 substrate. The coefficient of variation (CV) of CLint,h,2C8 was estimated to be 40%. Using this value, the CVs of AUC/Dose of other major CYP2C8 substrates, rosiglitazone and amodiaquine, were predicted to validate the estimated CV of CLint,h,2C8. As a result, the reported CVs of both substrates were within the 2.5-97.5 percentile range of the predicted CVs. Furthermore, the CVs of AUC/Dose of the CYP2C8 substrates loperamide and chloroquine, which are affected by renal clearance, were also successfully predicted. Combining this value with previously reported CVs of other CYPs, we were able to successfully predict the inter-individual variability in pharmacokinetics of various drugs in clinical.

KEYWORDS:

CYP2C8; Drug development; Human pharmacokinetics; Inter-individual variability; Monte carlo simulation

PMID:
29174535
DOI:
10.1016/j.dmpk.2017.09.001
[Indexed for MEDLINE]

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