title: Influence of CYP2C19 genotype on the pharmacokinetics of R483, a CYP2C19 substrate, in healthy subjects and type 2 diabetes patients.
abstract: OBJECTIVE
  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(0-24)) [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 AUC(0-24) 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.
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland. katrijn.bogman@roche.com
authors.forename: Katrijn
authors.initials: K
authors.lastname: Bogman
authors.forename: Mariabeth
authors.initials: M
authors.lastname: Silkey
authors.forename: Siew Pheng
authors.initials: SP
authors.lastname: Chan
authors.forename: Brian
authors.initials: B
authors.lastname: Tomlinson
authors.forename: Cornelia
authors.initials: C
authors.lastname: Weber
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D002214:Capsules; D002853:Chromatography, Liquid; D065731:Cytochrome P-450 CYP2C19; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics; D005260:Female; D005838:Genotype; D006442:Glycated Hemoglobin; D006801:Humans; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D013607:Tablets; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D044465:White People / Q000235:genetics*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D001786:Blood Glucose; D002214:Capsules; D065731:Cytochrome P-450 CYP2C19; D006442:Glycated Hemoglobin; D013607:Tablets; D045162:Thiazolidinediones; D013876:Thiophenes; C511003:5-((4-(2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy)benzo(2) thiophen-7-yl)methyl)-thiazolidine-2,4-dione; C517652:hemoglobin A1c protein, human; C045793:CYP2C19 protein, human