Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda.
OBJECTIVE
Polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been shown to influence nevirapine plasma concentrations in HIV-infected European Caucasians. Although nevirapine is used extensively in Africa, the influence of CYP2B6 genotype on nevirapine exposure has not been assessed in this population. We aimed to determine the influence of CYP2B6 genotype at position 516 on nevirapine trough concentrations in HIV-infected patients in Kampala, Uganda. Additional polymorphisms in the CYP and multidrug resistance protein-1 (MDR-1) genes were also assessed for their impact on nevirapine concentrations.


METHODS
The following genotypes were determined in all subjects using polymerase chain reaction-restriction fragment length polymorphism: CYP2B6 G516T, MDR-1 C3435T and G2677T, CYP3A4(*)1B and CYP3A5(*)3. Nevirapine plasma concentrations were determined using high-performance liquid chromatography in 23 HIV-infected patients who were generally healthy and had been taking nevirapine 200 mg twice daily for at least 14 days. Analysis of variance with post hoc testing was used to compare nevirapine concentrations among CYP2B6 genotype groups.


RESULTS
The median nevirapine trough concentration in individuals homozygous for the variant allele (TT) was 7607 ng/mL vs 4181 and 5559 ng/mL for GG and GT individuals, respectively (GG vs TT median ratio=1.82; P=0.011). The mean ratio for TT vs GG individuals (95% confidence interval) was 1.51 (1.18, 1.84). No associations were observed between the other polymorphisms studied and nevirapine concentrations.


CONCLUSIONS
CYP2B6 G516T significantly influenced nevirapine trough concentrations in HIV-infected patients in Uganda. Additional studies in larger patient populations are necessary to further define the potential clinical impact of these preliminary findings.
Penzak
S R
SR
Clinical Pharmacokinetics Research Laboratory, National Institutes of Health, Clinical Center Pharmacy Department, Bldg. 10, Room 1 N 257, Bethesda, MD 20892, USA. spenzak@cc.nih.gov
Kabuye
G
G
Mugyenyi
P
P
Mbamanya
F
F
Natarajan
V
V
Alfaro
R M
RM
Kityo
C
C
Formentini
E
E
Masur
H
H
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000097:blood* / Q000627:therapeutic use; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000097:blood* / Q000627:therapeutic use; D017678:Sex Distribution; D014454:Uganda / Q000453:epidemiology
D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating