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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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.
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.
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.
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.
KeywordsEfavirenz HIV/AIDS patients CYP2B6 polymorphism Pharmacokinetic modelling NONMEM
We are grateful to the Wilkins and Beatrice Infectious Disease Clinics for assistance with sample collection. We are grateful to AstraZeneca, Mölndal, DMPK Development Section and Dr. Xueqing Li for hosting Christopher Nyakutira for a 3-month bioanalytical training. Emmanuel Chigutsa is a recipient of a master’s fellowship from the International, Clinical and Operational Health Services Research Training Award (ICOHRTA) for AIDS and TB. Tafadzwa Mhlanga’s assistance with the CYP2B6*6 genotyping work is also acknowledged.
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