Secondary Logo

Institutional members access full text with Ovid®

Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

Tsamandouras, Nikolaos; Guo, Yingying; Wendling, Thierry; Hall, Stephen; Galetin, Aleksandra; Aarons, Leon

Pharmacogenetics and Genomics: January 2017 - Volume 27 - Issue 1 - p 27–38
doi: 10.1097/FPC.0000000000000252
ORIGINAL ARTICLES
Buy
SDC

Aim Ethnicity plays a modulating role in atorvastatin pharmacokinetics (PK), with Asian patients reported to have higher exposure compared with Caucasians. Therefore, it is difficult to safely extrapolate atorvastatin PK data and models across ethnic groups. This work aims to develop a population PK model for atorvastatin and its pharmacologically active metabolites specifically for the Japanese population. Subsequently, it aimed to identify genetic polymorphisms affecting atorvastatin PK in this population.

Methods Atorvastatin acid (ATA) and ortho-hydroxy-atorvastatin acid (o-OH-ATA) plasma concentrations, clinical/demographic characteristics and genotypes for 18 (3, 3, 1, 1, 7, 2 and 1 in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes, respectively) genetic polymorphisms were collected from 27 Japanese individuals (taking 10 mg atorvastatin once daily) and analysed using a population PK modelling approach.

Results The population PK model developed (one-compartment for ATA linked through metabolite formation to an additional compartment describing the disposition of o-OH-ATA) accurately described the observed data and the associated population variability. Our analysis suggested that patients carrying one variant allele for the rs2622604 polymorphism (ABCG2) show a 55% (95% confidence interval: 16–131%) increase in atorvastatin oral bioavailability relative to the value in individuals without the variant allele.

Conclusion The current work reports the identification in the Japanese population of a BCRP polymorphism, not previously associated with the PK of any statin, that markedly increases ATA and o-OH-ATA exposure. The model developed may be of clinical importance to guide dosing recommendations tailored specifically for the Japanese.

Supplemental Digital Content is available in the text.

aManchester Pharmacy School, Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK

bEli Lilly and Company, Indianapolis, Indiana, USA

Correspondence to Nikolaos Tsamandouras, PhD, Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 16, Room 16-451, Cambridge, MA 02139, USA Tel: +1 617 324 6065; fax: +1 617 253 2400; email: ntsaman@mit.edu

Received March 20, 2016

Accepted October 5, 2016

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.