A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single‐dose efavirenz population pharmacokinetics in Ugandans

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Efavirenz is metabolized by highly polymorphic enzymes, CYP2B6 and CYP3A. The effect of the different variant alleles on efavirenz population pharmacokinetics has not yet been fully explored.• CYP2B6*6 influences efavirenz steady-state pharmacokinetics. Together with sex it explains 11% of the between-subject variability in apparent oral clearance, but predictions could potentially be improved if additional alleles causing reduced drug metabolism were identified.• ABCB1 (3435C→T) may have effect on efavirenz single-dose and steady-state pharmacokinetics. WHAT THIS STUDY ADDS• A new polymorphism in ABCB1 gene (rs3842) and CYP2B6*11 in addition to sex and CYP2B6*6 genotype predict efavirenz single-dose pharmacokinetics.• A combined population pharmacogenetic/pharmacokinetic modelling approach allows determination and simulation of determinant factors for efavirenz single-dose pharmacokinetics based on data on gender, biochemical variables and genetic factors in relevant genes (a total of 30 SNPs in CYP2B6, ABCB1 and CYP3A4 genes) in Ugandan population. AIMSEfavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODSEfavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero-followed by first-order absorption. RESULTSApparent oral clearance (95% confidence interval) was 4 l h l -1 (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONSThe model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.

Pharmacogenetics of CYP2B6, CYP2A6 and UGT2B7 in HIV treatment in African populations: focus on efavirenz and nevirapine

“…In another Ugandan population, the 516G4T and 785A4G SNPs were found in 35.6 and 36.4% of the population, respectively (Mukonzo et al, 2009). Ngaimisi et al (2013) found the frequency of the 516G4T SNP to be significantly higher in Tanzanians (41.8%) than Ethiopians (31.4%), with 18.6% compared to only 8.7% homozygous individuals in the Tanzanian and Ethiopian populations, respectively.…”

“…An increase in efavirenz concentration is associated with an increase in the number of loss of function alleles, namely, CYP2B6 *6, *18, *20 and *27, in both Zimbabwean and Ugandan populations, with the number of either the 516G4T or 983T4C alleles having the greatest impact on increasing efavirenz concentrations (Jamshidi et al, 2010). Mukonzo et al (2009) reported a 21% lower oral clearance of efavirenz in another Ugandan population for individuals homozygous for the *6 allele. In a Bantu-speaking South African HIV-positive population, 35% had plasma efavirenz levels above the therapeutic range of 4 mg/ml, which is likely to be associated with toxicity (Swart et al, 2013).…”

“…A total of 1.9% and 4.7% of HIV-negative and HIV/AIDS patients, respectively, were homozygous for this SNP. The *11 allele was found in 13.6% of a Ugandan population, with homozygous individuals having a 20% lower apparent oral clearance of efavirenz (Mukonzo et al, 2009). The haplotypes *17, *19, *20 and *21 may also be considered to be African specific, as they have only been reported in populations of African origin; these haplotypes were absent in both the Asian and Caucasian populations studied (Klein et al, 2005).…”

CYP2B6*6 Screening; Potential Benefits and Challenges in HIV Therapy in Sub-Saharan Africa

“…Likewise, studies have also been done in African populations to evaluate the clinical implications of the CYP2B6*6 allele in the use of efavirenz [15][16][17][18], and nevirapine [19][20][21]. CYP2B6*6 has been associated with higher efavirenz plasma concentrations due to lower clearance rates, which may lead to CNS side effects [22,23].…”

Presence of Lamivudine or Emtricitabine Is Associated with Reduced Emergence of Nonnucleoside Reverse Transcriptase Inhibitor Mutations in an Efavirenz-Based Intermittent Antiretroviral Treatment Regimen

“…Halflives were highly variable (21,22), and as expected, they were shorter than the half-life reported after administration of a single dose (6), as a consequence of the autoinduction property of efavirenz. A genetic polymorphism of CYP2B6 G516T (4,6,10,14,16,17,20,23) leads to prolonged efavirenz half-lives and has been recognized as a factor that may explain the variability of efavirenz pharmacokinetics (5,21). Unfortunately, at the time the study was designed, blood samples were not collected for pharmacogenetics, and the ethnicity of patients was not recorded.…”