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

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 ph...

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Published in:European Journal of Clinical Pharmacology Vol. 66; no. 10; pp. 1005 - 1016
Main Authors: Bogman K, Silkey M, Chan SP, Tomlinson B, Weber C
Format: pictorial research tables/charts Journal Article
Published: Springer Nature Oct2010
Online Access:View this record in EBSCOhost
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        00316970
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      jtl: European Journal of Clinical Pharmacology
      issn: 00316970
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    pubinfo:
      dt: Oct2010
      vid: 66
      iid: 10
      pid: 237
      pub: Springer Nature
      place: New York, New York
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        105099568
        53703826
        10.1007/s00228-010-0840-3
        105099568
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      tig:
        atl: Influence of CYP2C19 genotype on the pharmacokinetics of R483, a CYP2C19 substrate, in healthy subjects and type 2 diabetes patients.
      aug:
        au:
          Bogman K
          Silkey M
          Chan SP
          Tomlinson B
          Weber C
        affil: F. Hoffmann-La Roche Ltd, Basel, Switzerland; katrijn.bogman@roche.com
      sug:
        subj:
          Thiazolidinediones Pharmacokinetics
          Diabetes Mellitus, Type 2 Familial and Genetic
          Genotype Evaluation
          Funding Source
          Polymorphism, Genetic
          White Persons
          Asians
          Human
          Diabetes Mellitus, Type 2 Ethnology
          Male
          Female
          Multicenter Studies
          Thiazolidinediones Metabolism
          Data Analysis Software
          Linear Regression
          Descriptive Statistics
          Analysis of Variance
          Sample Size
          Confidence Intervals
          Glycated Hemoglobin Blood
          Thiazolidinediones Administration and Dosage
          United States
          Canada
          Asia
          Genome, Human
          DNA Analysis
          ROC Curve
          One-Way Analysis of Variance
          Male
          Female
      ab: 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 (AUC) [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 AUC 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.
      pubtype: Academic Journal
      doctype:
        pictorial
        research
        tables/charts
        Journal Article
      ougenre: Article
    language: English
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