Pharmacogenetic markers of CYP2B6 associated with efavirenz plasma concentrations in HIV‐1 infected Thai adults

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Interindividual variability in efavirenz plasma concentrations is associated with CYP2B6 genetic polymorphisms.• Twenty‐nine different alleles of the CYP2B6 gene are listed. CYP2B6*6, *9, *16, *26, *27 and *28 carriers are reported to be associated with slower efavirenz oral clearance.• The allelic variant 516G>T is associated with diminished activity of CYP2B6 and high efavirenz plasma concentrations are associated with an increase risk of neuropsychological toxicity.WHAT THIS STUDY ADDS• This study identified three SNPs in the CYP2B6 gene which could potentially act as additional independent predictors of efavirenz plasma concentrations beyond that provided by the CYP2B6 c.516G>T polymorphism.• The GAC‐CYP2B6 haplotype (G516T/A785G/C21563T) is associated with higher plasma efavirenz concentrations in HIV‐infected Thai adults.• The CYP2B6 g.18492 T>C polymorphism was significantly associated with lower efavirenz concentrations than those with the homozygous wild‐type.AimsTo investigate the frequency of CYP2B6 polymorphisms and the influence of haplotype structure on plasma efavirenz concentrations in Thai adults with HIV‐1 infection.MethodsGenotyping of nine single nucleotide polymorphisms (SNPs, c.64C>T, c.499C>G, c.516G>T, c.785A>G, c.1375A>G, c.1459C>T, g.3003T>C, g.18492C>T and g.21563C>T) of CYP2B6 were performed using real‐time PCR‐based allelic discrimination on blood samples from 52 HIV‐infected adults who had received an efavirenz‐based regimen. Plasma efavirenz concentrations were measured by high performance liquid chromatography.ResultsThe minor allele frequencies for c.64C>T, c.516G>T, c.785A>G, g.3003C>T, g.18492T>C and g.21563C>T were 0.087, 0.365, 0.413, 0.308 and 0.356, respectively. However, no variant alleles were identified for three SNPs (c.499 C>G, c.1375 A>G and c.1459 C>T). Efavirenz plasma concentrations were significantly associated with c.516G>T (P= 0.0095), c.785A>G (P= 0.0017), g.21563C>T (P= 0.0036) and g.18492C>T (P= 0.0011). The composite CYP2B6 of three SNPs (c.516G ≥ T, c.785A ≥ G and g.21563C ≥ T) genotypes were significantly associated with higher efavirenz concentrations.ConclusionsOur data indicate that the GAC‐CYP2B6 haplotype is associated with higher plasma efavirenz concentrations in HIV‐infected Thai adults.

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

“…Overall, the allelic frequencies of the CYP2B6 SNPs detected in this study are consistent with a recent study in Thais (17). CYP2B6 499CϾG and 1375AϾG were the absent SNPs in this study, and CYP2B6 1459CϾT was rarely detected, which is consistent with previous reports from studies of Chinese patients (18,19) and Japanese patients (16).…”

“…Although the CYP2B6 516GϾT SNP is well known to be useful for predicting plasma efavirenz concentrations, little is known about the plasma efavirenz concentration prediction potential of the other two SNPs. Previous studies in Thais (13,17) and members of other ethnic groups (12,15,24) showed high plasma efavirenz concentrations in HIV-infected patients with the CYP2B6 516TT genotype while receiving rifampin. The frequency of this allele ranges from 15% in Asians up to 50% in Africans (11,15,25).…”

CYP2B6 18492T→C Polymorphism Compromises Efavirenz Concentration in Coinfected HIV and Tuberculosis Patients Carrying CYP2B6 Haplotype *1/*1

“…Note that the means of efavirenz concentrations in the patients who carried heterozygous and homozygous mutants were 1.7 mg/liter and 1.2 mg/liter, respectively. Compared to a previous study in patients with HIV monoinfection, efavirenz concentrations of the corresponding patients were 2.0 mg/liter and 1.7 mg/liter, respectively (19). Patients in the current study were therefore more vulnerable to suboptimal efavirenz concentrations.…”

“…SNP 499C¡G was associated with high plasma efavirenz concentrations in Japanese subjects, and the remaining three SNPs, i.e., 64C¡T, 1375A¡G, and 1459C¡T, were reported in Chinese subjects (18). The CYP2B6 18492T¡C SNP was identified using HapMap (www.hapmap.org) data on Japanese and Han Chinese populations with an r 2 value of Ͼ0.8 (19). SNPs were genotyped at the Laboratory for Pharmacogenomics and Personalized Medicine, Ramathibodi Hospital, Mahidol University.…”

Hepatocyte CYP2B6 Can Be Expressed in Cell Culture Systems by Exerting Physiological Levels of Shear: Implications for ADME Testing

“…It is increasingly apparent that many polymorphisms in CYP2B6 are both relatively common and have a substantive effect on rates of drug metabolism [3, 6, 36, 37]. Hence, in screening for CYP2B6-mediated drug metabolism, it is important not only to document expression but also to define the haplotype being studied.…”