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Influence of CYP2C19 genotype on the pharmacokinetics of R483, a CYP2C19 substrate, in healthy subjects and type 2 diabetes patients

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objectives

R483 is a thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist with anti-diabetic properties and also a cytochrome P450 2C19 (CYP2C19) substrate. The aim of the clinical studies reported here was to investigate the influence of the CYP2C19 genotype on the pharmacokinetics (PK) of R483 in healthy subjects and in type 2 diabetes mellitus (T2DM) patients.

Methods

Data came from two clinical studies, one including 58 Japanese and Caucasian healthy subjects and another including 93 Asian T2DM patients. All subjects received multiple doses of R483, 20 mg once daily for the healthy subjects and 12 mg once daily for the T2DM patients. Blood samples were taken up to 24 h after the last dose to determine plasma concentrations of R483 and its major metabolites.

Results

Poor metabolizers (PMs; CYP2C19*2/*2 or *2/*3 or *3/*3) had a higher plasma exposure and a lower clearance of the parent drug than extensive metabolizers (EMs; CYP2C19*1/*1 or *1/*2 or *1/*3). The homozygous PM/EM ratio for the area under the plasma concentration–time curve (AUC0–24) [95% confidence interval] was 3.9 [2.7–5.7] for healthy subjects versus 2.0 [1.5–2.6] in T2DM patients. The heterozygous EMs were all T2DM patients, the PM/EM ratio for AUC0–24 was 1.5 [1.2–1.8]. The dose-normalized exposure to R483 was 1.2- (for PMs) and 2.4-fold (for EMs) higher in T2DM patients than in healthy subjects. R483 was well tolerated in both studies.

Conclusions

The plasma exposure to R483 was significantly higher in PMs than in EMs. R483 exhibits different PK in healthy subjects and T2DM patients, and the difference in exposure between EM and PM was less pronounced in T2DM patients than in healthy subjects. Factors such as diabetes condition and age may influence the metabolism of R483. This knowledge allowed for a realistic dose recommendation for poor metabolizer T2DM patients.

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Acknowledgments and conflict of interest statement

The reported studies were supported by F. Hoffmann–La Roche Ltd. The authors that are employees of F. Hoffmann–La Roche Ltd are thus eligible for stock options of the company. The authors were responsible for the analysis and interpretation of the data and the preparation of the manuscript. Chan S.P. and Tomlinson B. have no financial or personal relationships that could be perceived as influencing the research described.

The authors want to acknowledge all investigators and their staff for their commitment and enthusiasm.

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Authors and Affiliations

  1. F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Katrijn Bogman, Mariabeth Silkey & Cornelia Weber

  2. University of Malaya, Kuala Lumpur, Malaysia

    Siew Pheng Chan

  3. The Chinese University of Hong Kong, Shatin, Hong Kong

    Brian Tomlinson

Authors
  1. Katrijn Bogman
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  2. Mariabeth Silkey
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  3. Siew Pheng Chan
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  4. Brian Tomlinson
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  5. Cornelia Weber
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Corresponding author

Correspondence to Katrijn Bogman.

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Bogman, K., Silkey, M., Chan, S.P. et al. Influence of CYP2C19 genotype on the pharmacokinetics of R483, a CYP2C19 substrate, in healthy subjects and type 2 diabetes patients. Eur J Clin Pharmacol 66, 1005–1015 (2010). https://doi.org/10.1007/s00228-010-0840-3

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  • DOI: https://doi.org/10.1007/s00228-010-0840-3

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