CYP2B6 (c.516G→T) and CYP2A6 (*9B and/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV‐infected patients

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cytochrome P450 (CYP) 2B6 polymorphisms, particularly c.516G→T, are strongly associated with plasma efavirenz concentrations, but do not entirely explain interindividual variability in efavirenz exposure.• In vitro data suggest that CYP2A6 is involved in the metabolism of efavirenz.• Rifampicin can induce the function and activity of the main metabolizing for efavirenz and causes small (22-26%) reductions in efavirenz area under the curve during co-administration, although with wide interindividual variability. WHAT THIS STUDY ADDS• Identifies CYP2B6 516G→T polymorphism and carriers of CYP2A6*9B and/or *17 variants as independent predictors of efavirenz mid-dose concentration in human immunodeficiency virus-infected patients.• Factors such as concurrent therapy with rifampicin-containing tuberculosis regimen, gender and body mass index had no a significant influence on efavirenz mid-dose concentration.• Provides in vivo evidence that CYP2A6 is likely to be involved in the metabolism of efavirenz. AIMSInterindividual variability in efavirenz pharmacokinetics is not entirely explained by the well-recognized CYP2B6 516G→T single nucleotide polymorphism. The aim of this study was to determine whether polymorphisms in the CYP2A6 gene can be used to enhance the predictability of efavirenz concentrations in human immunodeficiency virus (HIV)-infected native African patients. METHODSMid-dose efavirenz plasma concentrations were determined at 4 and 8 weeks following initiation of antiretroviral therapy in 65 HIV-infected Ghanaian patients. Selected CYP2B6 and CYP2A6 genotypes were determined by commercial 5′-nuclease assays. Relationships between averaged 4-and 8-week mid-dose efavirenz concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches including gene-gene interactions. RESULTSCYP2B6 c.516G→T, CYP2B6 c.983T→C, CYP2A6*9B and CYP2A6*17 allele frequencies were 45, 4, 5 and 12%, respectively. Rifampicin therapy, gender, age and body mass index had no significant influence on efavirenz mid-dose concentrations. Median efavirenz concentrations were more than five times higher (P < 0.001) in patients with CYP2B6 c.516TT genotype compared with GG and GT genotypes. Although none of the CYP2A6 genotypes was associated with altered efavirenz concentrations individually, CYP2A6*9B and/or CYP2A6*17 carriers showed a 1.8 times higher median efavirenz concentration (P = 0.017) compared with noncarriers. Multiple linear regression analysis indicated that the CYP2B6 c.516G→T polymorphism and CYP2A6 slow-metabolizing variants accounted for as much as 36 and 12% of the total variance in efavirenz concentrations, respectively. CONCLUSIONSOur findings support previous work showing efavirenz oxidation by CYP2A6, and suggest that both CYP2A6 and CYP2B6 genotyping may be useful for predicting efavirenz plasma concentrations.

Impact of Pharmacogenetic Markers ofCYP2B6, Clinical Factors, and Drug-Drug Interaction on Efavirenz Concentrations in HIV/Tuberculosis-Coinfected Patients

“…CYP3A4 *1B was associated with lower efavirenz clearance. Neither CYP3A4 nor CYP2A6 SNPs were examined in this study; however, a relatively weak association between their variants and efavirenz concentrations was previously shown (13,29). Third, data corresponding to the factor "receiving rifampin" did not reach a significant level, although this factor was found to be associated with low efavirenz concentrations in a previous study (30).…”

CYP2B6 516 G>T polymorphism and side effects of the central nervous system in HIV-positive individuals under Efavirenz treatment: Study of a sample from southern Brazil

“…Moreover, it was reported that the difference in the expression and function of the CYP2B6 gene cause great variability in the response to EFV. The CYP2B6 516 G>T polymorphism is one of the most important factors responsible for increased plasma concentrations of the drug and the neuropsychiatric effects associated with EFV (Kwara et al 2008, Gounden et al 2010). …”

“…A transversion of G to T allele in exon 4 (516 G>T, rs3745274) of the CYP2B6 gene contributes to reduced clearance of EFV and its increased concentration in plasma, causing side effects in the CNS and indicating decreased enzyme function in vivo (Kwara et al 2008, Gounden et al 2010, Rakhmanina and van den Anker 2010. In addition, an association is noted between the slow and intermediate metabolizer phenotypes and virological suppression (Frasco et al 2012).…”

Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

“…Nowadays, analysis of the influence of genetic factors is becoming increasingly important, because the existence of genetic polymorphisms in genes coding for proteins involved in the metabolism or transport of ARVs may alter protein activity and therefore explain, in part, the high interpatient PK variability of these drugs (12,25,40,46). Cytochrome CYP2B6 is the main enzyme responsible for hydroxylation (60), with the partial involvement of CYP3A4/ CYP3A5 and, according to recent studies, CYP2A6 (1,15,31,32). In addition, several other CYPs, including CYP2D6, CYP2C9, CYP2C19, and CYP2C8, may also contribute, although their individual roles in EFV metabolism are not clearly defined (1,16,22,35,50,57).…”