Dataset Information

Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants.

ABSTRACT: Prior candidate gene studies have associated CYP2B6 516G?T [rs3745274] and 983T?C [rs28399499] with increased plasma efavirenz exposure. We sought to identify novel variants associated with efavirenz pharmacokinetics.Antiretroviral therapy-naive AIDS Clinical Trials Group studies A5202, A5095, and ACTG 384 included plasma sampling for efavirenz pharmacokinetics. Log-transformed trough efavirenz concentrations (Cmin) were previously estimated by population pharmacokinetic modeling. Stored DNA was genotyped with Illumina HumanHap 650Y or 1MDuo platforms, complemented by additional targeted genotyping of CYP2B6 and CYP2A6 with MassARRAY iPLEX Gold. Associations were identified by linear regression, which included principal component vectors to adjust for genetic ancestry.Among 856 individuals, CYP2B6 516G?T was associated with efavirenz estimated Cmin (P=8.5×10). After adjusting for CYP2B6 516G?T, CYP2B6 983T?C was associated (P=9.9×10). After adjusting for both CYP2B6 516G?T and 983T?C, a CYP2B6 variant (rs4803419) in intron 3 was associated (P=4.4×10). After adjusting for all the three variants, non-CYP2B6 polymorphisms were associated at P-value less than 5×10. In a separate cohort of 240 individuals, only the three CYP2B6 polymorphisms replicated. These three polymorphisms explained 34% of interindividual variability in efavirenz estimated Cmin. The extensive metabolizer phenotype was best defined by the absence of all three polymorphisms.Three CYP2B6 polymorphisms were independently associated with efavirenz estimated Cmin at genome-wide significance, and explained one-third of interindividual variability. These data will inform continued efforts to translate pharmacogenomic knowledge into optimal efavirenz utilization.

SUBMITTER: Holzinger ER

PROVIDER: S-EPMC3614365 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants.

Holzinger Emily R ER Grady Benjamin B Ritchie Marylyn D MD Ribaudo Heather J HJ Acosta Edward P EP Morse Gene D GD Gulick Roy M RM Robbins Gregory K GK Clifford David B DB Daar Eric S ES McLaren Paul P Haas David W DW

Pharmacogenetics and genomics 20121201 12

<h4>Objectives</h4>Prior candidate gene studies have associated CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499] with increased plasma efavirenz exposure. We sought to identify novel variants associated with efavirenz pharmacokinetics.<h4>Materials and methods</h4>Antiretroviral therapy-naive AIDS Clinical Trials Group studies A5202, A5095, and ACTG 384 included plasma sampling for efavirenz pharmacokinetics. Log-transformed trough efavirenz concentrations (Cmin) were previously estimated by po ...[more]

PMID: 23080225

Similar Datasets

Project description:Efavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 ?g/ml may result in virologic failure and above 4 ?g/ml, may result in central nervous system adverse effects. This study used population pharmacokinetics modeling to explore the influence of demographic and pharmacogenetic factors including efavirenz-rifampicin interaction on EFV pharmacokinetics, towards safer dosing of EFV.Patients receiving an EFV-based regimen for their antiretroviral therapy and a rifampicin-containing anti-TB regimen were recruited. EFV plasma concentrations were measured by HPLC and genomic DNA genotyped for variants in the CYP2B6, CYP2A6 and ABCB1 genes. All patients were evaluated for central nervous system adverse effects characterised as sleep disorders, hallucinations and headaches using the WHO ADR grading system. A pharmacokinetic model was built in a forward and reverse procedure using nonlinear mixed effect modeling in NONMEM VI followed by model-based simulations for optimal doses.CYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance. Patients with the CYP2B6*6TT genotype had a 63% decrease in EFV clearance despite their CYP2B6*18 genotypes with females having 22% higher clearance compared to males. There was a 21% increase in clearance for every 10 kg increase in weight. The effect of TB/HIV co-treatment versus HIV treatment only was not statistically significant. No clinically relevant association between CYP2B6 genotypes and CNS adverse effects was seen, but patients with CNS adverse effects had a 27% lower clearance compared to those without. Model- based simulations indicated that all carriers of CYP2B6*6 TT genotype would be recommended a dose reduction to 200 mg/day, while the majority of extensive metabolisers may be given 400 mg/day and still maintain therapeutic levels.This study showed that screening for CYP2B6 functional variants has a high predictability for efavirenz plasma levels and could be used in prescribing optimal and safe EFV doses.

Project description:ObjectivesWe evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations.MethodsART naïve HIV patients from Ethiopia (n?=?285) and Tanzania (n?=?209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done.ResultPatient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p?=?0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p?=?0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p?=?0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART.ConclusionWe report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations.

Dataset Information

Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants.

Publications

Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets