Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis

Clinical Pharmacokinetics, Jun 2017

Background Ethnic variability in the pharmacokinetics of organic anion transporting polypeptide (OATP) 1B1 substrates has been observed, but its basis is unclear. A previous study hypothesizes that, without applying an intrinsic ethnic variability in transporter activity, allele frequencies of transporters cannot explain observed ethnic variability in pharmacokinetics. However, this hypothesis contradicts the data collected from compounds that are OATP1B1 substrates but not breast cancer resistance protein (BCRP) substrates. Objective The objective of this study is to evaluate a hypothesis that is physiologically reasonable and more consistent with clinical observations. Methods We evaluated if allele frequencies of two transporters (OATP1B1 and BCRP) are key contributors to ethnic variability. In this hypothesis, the same genotype leads to the same activity independent of ethnicity, in contrast to the previous hypothesis of intrinsic ethnic variability in OATP1B1 activity. As a validation, we perform mechanistic pharmacokinetic modeling for SLCO1B1 (encoding OATP1B1) and ABCG2 (encoding BCRP) genotyped pharmacokinetic data from 18 clinical studies with healthy Caucasian and/or Asian subjects. Results Simulations based on the current hypothesis reasonably describe SLCO1B1 and ABCG2 genotyped pharmacokinetic time course data for five transporter substrates (atorvastatin, pitavastatin, pravastatin, repaglinide, and rosuvastatin) in Caucasian and Asian populations. Conclusion This hypothesis covers the observations that can (e.g., ethnic differences in rosuvastatin pharmacokinetics) or cannot (e.g., lack of differences for pitavastatin pharmacokinetics) be explained by the previous hypothesis. It helps to characterize sources of ethnic variability and provides a foundation for predicting ethnic variability in transporter substrate pharmacokinetics.

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Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis

Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis Rui Li 0 1 Hugh A. Barton 0 1 Rui Li Rui.Li 0 1 @pfizer.com 0 1 0 Translational Modeling and Simulation, Biomedicine Design, World Wide Research and Development, Pfizer Inc. , Groton, CT , USA 1 Systems Modeling and Simulation, Medicine Design, World Wide Research and Development, Pfizer Inc. , Cambridge, MA , USA Background Ethnic variability in the pharmacokinetics of organic anion transporting polypeptide (OATP) 1B1 substrates has been observed, but its basis is unclear. A previous study hypothesizes that, without applying an intrinsic ethnic variability in transporter activity, allele frequencies of transporters cannot explain observed ethnic variability in pharmacokinetics. However, this hypothesis contradicts the data collected from compounds that are OATP1B1 substrates but not breast cancer resistance protein (BCRP) substrates. Objective The objective of this study is to evaluate a hypothesis that is physiologically reasonable and more consistent with clinical observations. Methods We evaluated if allele frequencies of two transporters (OATP1B1 and BCRP) are key contributors to ethnic variability. In this hypothesis, the same genotype leads to the same activity independent of ethnicity, in contrast to the previous hypothesis of intrinsic ethnic variability in OATP1B1 activity. As a validation, we perform mechanistic pharmacokinetic modeling for SLCO1B1 (encoding OATP1B1) and ABCG2 (encoding BCRP) genotyped pharmacokinetic data from 18 clinical studies with healthy Caucasian and/or Asian subjects. Results Simulations based on the current hypothesis reasonably describe SLCO1B1 and ABCG2 genotyped pharmacokinetic time course data for five transporter substrates (atorvastatin, pitavastatin, pravastatin, repaglinide, and rosuvastatin) in Caucasian and Asian populations. Conclusion This hypothesis covers the observations that can (e.g., ethnic differences in rosuvastatin pharmacokinetics) or cannot (e.g., lack of differences for pitavastatin pharmacokinetics) be explained by the previous hypothesis. It helps to characterize sources of ethnic variability and provides a foundation for predicting ethnic variability in transporter substrate pharmacokinetics. Key Points Ethnic variability in the pharmacokinetics of organic anion-transporting polypeptide (OATP) 1B1 substrates has been observed for some drugs, but the basis of the differences has been unclear. A previous hypothesis proposing intrinsic ethnic variability in activity was inconsistent with data collected from compounds that are OATP1B1 substrates but not breast cancer resistance protein (BCRP) substrates (e.g., pitavastatin and repaglinide). We evaluated an alternative hypothesis for ethnic variability in the pharmacokinetics of transporter substrates based upon allelic frequencies of both OATP1B1 and BCRP. Simulations based on this hypothesis can reasonably describe OATP1B1 or BCRP genotyped pharmacokinetic time course data in Caucasian, Chinese, Japanese, and Korean populations. The hypothesis and mathematical model developed in this study provide insights into the sources of ethnic variability and provide a foundation for prospectively predicting ethnic variability in the pharmacokinetics of transporter substrates. 1 Introduction Many efforts have been undertaken in the past decade to understand the roles played by transporters in drug pharmacokinetics, pharmacodynamics, and toxicity. Their importance in drug absorption, disposition, and elimination has been recognized by academia, industry, and regulatory agencies. Among drug transporters, organic anion transporting polypeptide (OATP) 1B1, a hepatic uptake transporter encoded by gene SLCO1B1, has probably received the most attention. Previous studies have shown that SLCO1B1 genetic variations may lead to changes in OATP1B1 activity in both in-vitro and clinical studies [ 1 ]. In addition, pharmacokinetic profiles of OATP1B1 substrates differ among ethnic groups (particularly Asian and Caucasian populations) [ 2 ]. These differences contribute to the inter-individual variability in the clinical pharmacokinetics of drugs, raising questions of how these observations may guide future clinical practice to achieve pharmacological effects while avoiding toxicological effects in each patient. For example, should the dose be adjusted for ethnic differences, genetic variations, or both? To answer these questions, it is important first to understand the mechanism governing the observations. A previous report states that with the same genotype of SLCO1B1, OATP1B1 activity in an Asian population is about half of that in a Caucasian population, suggesting that along with allele frequencies of transporter genes, an intrinsic ethnic variability in activity could be an independent source of pharmacokinetic variati (...truncated)


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Rui Li, Hugh A. Barton. Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis, Clinical Pharmacokinetics, 2017, pp. 1-13, DOI: 10.1007/s40262-017-0568-7