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

• Published in: Clinical pharmacokinetics Vol. 57; no. 4; pp. 491 - 503
• Main Authors: Li, Rui, Barton, Hugh A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2018; Springer Nature B.V
• Subjects: Asian Continental Ancestry Group - genetics; Atorvastatin - administration & dosage; Atorvastatin - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; Breast cancer; Carbamates - administration & dosage; Carbamates - pharmacokinetics; Computer Simulation; Cultural differences; Drug dosages; European Continental Ancestry Group - genetics; Gene Frequency; Genes; Genotype; Haplotypes; Healthy Volunteers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Hypotheses; Internal Medicine; Liver-Specific Organic Anion Transporter 1 - genetics; Liver-Specific Organic Anion Transporter 1 - metabolism; Medicine; Medicine & Public Health; Metabolism; Minority & ethnic groups; Models, Biological; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Original; Original Research Article; Pharmacogenomic Variants; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Phenotype; Piperidines - administration & dosage; Piperidines - pharmacokinetics; Polypeptides; Population genetics; Pravastatin - administration & dosage; Pravastatin - pharmacokinetics; Proteins; Quinolines - administration & dosage; Quinolines - pharmacokinetics; Rosuvastatin Calcium - administration & dosage; Rosuvastatin Calcium - pharmacokinetics; Studies
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-017-0568-7

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.