Prediction of inter-individual variability on the pharmacokinetics of CYP2C8 substrates in human |
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| Affiliation: | 1. Chugai Pharmabody Research Pte. Ltd., Singapore;2. Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan;3. Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Yokohama, Japan;4. Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Japan;1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;2. RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan;3. Osaka City University Graduate School of Medicine, 1–4–3 Asahimachi, Abeno–ku, Osaka 545–8585, Japan;4. Osaka City University Hospital, Center for Drug & Food Clinical Evaluation, 1–2–7 Asahimachi, Abeno–ku, Osaka 545–0051, Japan;5. RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan;6. Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan;7. Clinical Research Center, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan;8. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan;9. Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, Yokohama Bio Industry Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan;1. School of Pharmacy, China Medical University, Taichung 404, Taiwan;2. Department of Pharmacy, China Medical University Hospital, Taichung 404, Taiwan;3. Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 404, Taiwan;1. Pharmacokinetic Research Laboratories, Ono Pharmaceutical Company, Ltd., Ibaraki, Japan;2. Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Kanagawa, Japan;3. Oncology Clinical Development Planning, Ono Pharmaceutical Company, Ltd., Osaka, Japan;4. Translational Medicine Center, Ono Pharmaceutical Company, Ltd., Osaka, Japan;1. Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan;2. Tokyo New Drug Research Laboratories, Kowa Co., Ltd., Higashimurayama, Tokyo, 189-0022, Japan;3. Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki, 210-0821, Japan |
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| 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. |
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| Keywords: | CYP2C8 Inter-individual variability Monte carlo simulation Human pharmacokinetics Drug development |
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