Efavirenz Dosing: Influence of Drug Metabolizing Enzyme Polymorphisms and Concurrent Tuberculosis Treatment. Issue 3 (April 2015)

• Record Type: Journal Article
• Authors: Gengiah, Tanuja N; Botha, Julia H; Yende-Zuma, Nonhlanhla; Naidoo, Kogieleum; Karim, Salim S Abdool
• Is Part Of: Antiviral therapy. Volume 20:Issue 3(2015)
• Page Start: 297
• Page End: 306
• Publication Date: 2015-04
• Subjects: Antiviral agents -- Periodicals; Antiviral Agents -- therapeutic use; Virus Diseases -- therapy; Viruses -- drug effects; Antiviral agents; Periodical; Electronic journals; Periodicals; 616.9106
• DOI: 10.3851/IMP2877
• Languages: English
• ISSNs: 1359-6535

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 (C were measured min ) 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 C. min Results: During TB treatment, median EFV C was 3.2 min (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 C was 2.0 (1.4-3.5) μg/ml. Minor allele min 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.