Effect of Cytochrome P450 2C8*3 on the Population Pharmacokinetics of Pioglitazone in Healthy Caucasian Volunteers.
Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, is indicated for the treatment of type 2 diabetes. Pioglitazone undergoes hepatic metabolism by cytochrome P450 2C8 (CYP2C8) and interindividual variability exists in pioglitazone disposition and response. In previous analyses, it has been shown that the CYP2C8*3 polymorphism significantly impacts pioglitazone pharmacokinetics in humans. The purpose of this investigation was to develop a population pharmacokinetic model using nonlinear mixed effects analysis to evaluate and quantify the effect of CYP2C8*3, demographic, and clinical variables on interindividual variability in pioglitazone pharmacokinetics in nondiabetic adults. Data were obtained from 31 healthy volunteers (n=16 CYP2C8*1/*1, n=15 CYP2C8*3 carriers) who had previously participated in the monotherapy phase of a pioglitazone drug-drug interaction study. Participants received a single 15 g dose of pioglitazone followed by a 48-h sampling period. A two-compartment model with first order absorption and elimination (Akaike Information Criteria (AIC)=2889) showed a better fit for pioglitazone than a one-compartment model (AIC=3008). Covariate analysis revealed that CYP2C8*3 had a significant effect on pioglitazone central compartment clearance (CL/F; p=0.0005) and intercompartmental clearance (Q/F; p=0.004). Pioglitazone CL/F and Q/F were 52% and 286% higher, respectively, in carriers of the CYP2C8*3 allele than in CYP2C8*1 homozygotes. Furthermore, inclusion of CYP2C8*3 as a covariate on CL/F and Q/F decreased interindividual variability in these parameters by 5.2% and 14%, respectively. Other variables (e.g., sex, body weight) were not significant covariates on pioglitazone pharmacokinetics in the model. In summary, CYP2C8*3 significantly affected pioglitazone CL/F, Q/F, and interindividual variability in these parameters in this healthy volunteer cohort.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of Colorado Skaggs, Aurora, CO 80045, USA.
Rajendra
R
Kadam
David
D
Bourne
Uday
U
Kompella
Christina
C
Aquilante
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics*; D044465:White People; D055815:Young Adult
D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000077205:Pioglitazone