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Eur J Clin Pharmacol. 2008 Apr;64(4):357-65. Epub 2007 Dec 5.

High prevalence of the CYP2B6 516G-->T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe.

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1
Department of DMPK & BAC, African Institute of Biomedical Science and Technology (AiBST), P.O.Box 2294, Harare, Zimbabwe.

Abstract

OBJECTIVE:

The study sought to investigate the relationship between efavirenz exposure and the CYP2B6 516G-->T(*6) genotype in HIV/AIDS outpatients, using pharmacokinetic modelling and simulation.

METHODS:

Blood samples where obtained from 74 outpatients treated with a combination regimen including 600 mg efavirenz daily for a duration of at least 3 weeks at clinics in Harare, Zimbabwe. The subjects were genotyped for the major CYP2B6 variant, CYP2B6*6, associated with reduced enzyme activity, using a PCR-RFLP method. Efavirenz plasma concentrations were determined by HPLC-UV. Population pharmacokinetic modelling and simulation of the data were performed in NONMEM VI.

RESULTS:

A high allele frequency of the CYP2B6*6 allele of 49% was observed. Efavirenz plasma concentrations were above 4 mg/L in 50% of the patients. Genotype and sex were identified as predictive covariates of efavirenz disposition. Pharmacokinetic parameter estimates indicate that a dose reduction to 400 mg efavirenz per day is possible in patients homozygous for the CYP2B6*6 genotype without compromising therapeutic efficacy.

CONCLUSION:

The CYP2B6*6 allele occurs at a high frequency in people of African origin and is associated with high efavirenz concentrations. Simulations indicate that an a priori 35% dose reduction in homozygous CYP2B6*6 patients would maintain drug exposure within the therapeutic range in this group of patients. Our preliminary results suggest the conduct of a prospective clinical dose optimization study to evaluate the utility of genotype-driven dose adjustment in this population.

PMID:
18057928
DOI:
10.1007/s00228-007-0412-3
[Indexed for MEDLINE]
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