2008 - Marseille - France

PAGE 2008: Applications- Anti-infectives
María José García Sánchez

Population Pharmacokinetics of Efavirenz in HIV-infected patients: Pharmacogenetic analysis

García MJ, Santos Buelga D, Cabrera S, Fernandez de Gatta MM, Domínguez-Gil

(1) Department of Pharmacy & Pharmaceutical Technology, University of Salamanca, Salamanca, Spain; (2) Pharmacy Service, University Hospital of Salamanca, Salamanca, Spain

Objectives: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, is often used in highly active antiretroviral therapy for the management of both treatment-naïve and treatment-experienced patients. The metabolism of EFV is mediated by CYP2B6 and CYP3A4 isoenzymes. The polymorphism exhibited by these isoenzymes as well as the proteins involved in drug transport may partly explain the pharmacokinetic inter-patient variability. The present study analyzes the influence of genetic polymorphism of CYP2B6 and CYP3A4 isoenzymes, and MDR-1 gene (codifying the P-glycoprotein transporter) on the EFV pharmacokinetics in HIV-infected patients.

Methods: The analysis was conducted in a total of 375 EFV concentrations from 131 HIV-infected subjects from the outpatient unit of the University Hospital of Salamanca, Spain, treated with EFV at the dose of 600 mg/day. EFV concentrations were assessed quantitatively by HPLC with UV detection. So far only 31 study participants were genotyped with PHARMAchip® DNAchip (PROGENIKA BIOPHARMA, Derio, Spain) which permits the analysis of 91 genetic polymorphisms from 33 genes, including CYP2B6, CYP3A4 and MDR-1 genes. The population analysis was performed using the non-linear mixed effects modeling approach implemented in NONMEM. To data adjustment, a one-compartment model with first-order absorption was assumed and FOCE estimation was used throughout. In addition to genetic characteristics, other covariates analyzed were patient age, weight, sex and body mass index (BMI).

Results: For the CYP2B6 (G516T), 9 patients were heterozygotes (GT) and 6 patients were homozygotes for the mutant allele (TT). With respect the CYP3A4 (*1/B), four patients showed polymorphism, being 3 heterozygotes (*1B) and 1 homozygote for the mutant allele (*B/B). Finally regarding MDR1 (C3435T), 16 patients were heterozygotes (CT) and 6 patients were homozygotes for the mutant allele (TT).The inclusion in the model of GT, TT and MDR1 polymorphisms and consideration of BMI for patients who showed low body mass (BMI<25) reduce both CL inter-subject and residual variabilities more than 30% from the basic to final model. Patients showing GT and TT polymorphisms exhibited around of 30 % and 75% lower EFV clearance, respectively, while heterozygote patients for MDR1 showed CL increases around of 20% compared to patients without these polymorphisms. These results were similar  when the analysis was performed in the full population and also when only the genotyped patients were considered.

Conclusions: These preliminary results indicate that single o double alterations in CYP2B6 alleles, as well as double alterations in MDR-1 alleles and low BMI, influence EFV clearance and emphasize the need for dose individualization according these variables to avoid inadequate treatment response to EFV.

Reference: PAGE 17 (2008) Abstr 1441 [www.page-meeting.org/?abstract=1441]
Poster: Applications- Anti-infectives