Efavirenz dosing: influence of drug metabolizing enzyme polymorphisms and concurrent tuberculosis treatment

Abstract

Background: Rifampicin-based tuberculosis (TB) treatment alters efavirenz (EFV) clearance. Polymorphisms in important drug metabolizing enzymes and the implications for EFV dosing were investigated.

Methods: Trough EFV concentrations (Cmin) were measured in 54 South African black patients. During TB treatment, EFV dose was 600 mg in patients <50 kg or 800 mg if ≥50 kg. Off TB treatment it was 600 mg. Polymorphisms in CYP2B6, CYP2A6 and UGT2B7 enzymes were sequenced. A multivariate generalized estimating equations model was fitted to assess predictors of high median EFV Cmin.

Results: During TB treatment, median EFV Cmin was 3.2 (IQR 2.6-6.3) µg/ml and 3.3 (2.4-9.5) µg/ml in the 800 mg and 600 mg groups, respectively. After TB treatment EFV Cmin was 2.0 (1.4-3.5) µg/ml. Minor allele frequencies for CYP2B6 516G→T, 785A→G, 983T→C, UGT2B7-372G→A, CYP2A6*9B and CYP2A6*17 were 0.31, 0.33, 0.23, 0.29, 0.10 and 0.02, respectively. Haplotypes CYP2B6*6 and CYP2B6*18 were found in 38.9% and 25.9% of patients, respectively. Polymorphisms in all three CYP2B6 genes studied (516T-785G-983C) were present in 11.1% of patients and in this group median EFV Cmin was 19.2 (IQR 9.5-20) µg/ml during and 4.7 (IQR 3.5-5.6) µg/ml after TB treatment. The presence of TB treatment and composite genotypes CYP2B6 516 GT/TT, CYP2B6 983 TC/CC and CYP2A6*9B carrier status predicted median EFV Cmin>4 µg/ml. Adverse events due to high EFV concentrations were rare.

Conclusions: Because polymorphisms of EFV metabolizing enzymes are frequent and are associated with elevated EFV concentrations in this population, EFV dose increases are unnecessary when concomitant rifampicin-containing TB treatment is prescribed.