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


CONCLUSIONS
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.
Department of DMPK & BAC, African Institute of Biomedical Science and Technology (AiBST), P.O.Box 2294, Harare, Zimbabwe.
Christopher
C
Nyakutira
Daniel
D
Röshammar
Emmanuel
E
Chigutsa
Prosper
P
Chonzi
Michael
M
Ashton
Charles
C
Nhachi
Collen
C
Masimirembwa
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D000328:Adult; D000465:Algorithms; D000480:Alkynes; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D015233:Models, Statistical; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011153:Population; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012737:Sex Factors; D015030:Zimbabwe / Q000453:epidemiology
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz