JAC Advance Access originally published online on October 6, 2009
Journal of Antimicrobial Chemotherapy 2009 64(6):1265-1273; doi:10.1093/jac/dkp351
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Original research |
Influence of CYP2B6 polymorphisms on the persistence of plasma nevirapine concentrations following a single intra-partum dose for the prevention of mother to child transmission in HIV-infected Thai women
1 Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 2 Harvard School of Public Health, Boston, MA, USA 3 Institut de Recherche pour le Développement, URI-174, Program for HIV Prevention and Treatment, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand 4 Medical Genetics Section, National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand 5 Pediatric Pharmacology Research Unit, University of California, San Diego, CA, USA
Received 10 July 2009; returned 1 August 2009; revised 28 August 2009; accepted 31 August 2009
* Corresponding author. Tel: +66-2201-2754; Fax: +66-2201-1470; E-mail: rawct{at}mahidol.ac.th
Objectives: To investigate the association of single nucleotide polymorphisms (SNPs) with nevirapine concentrations following intra-partum single-dose nevirapine.
Methods: Plasma and DNA samples were obtained from 330 HIV-infected Thai women who received intra-partum single-dose nevirapine in the PHPT-2 clinical trial to prevent perinatal HIV transmission. Nine SNPs within CYP2B6, CYP3A4 and ABCB1 were genotyped by real-time PCR. Nevirapine plasma concentrations were determined by HPLC and used in a population pharmacokinetic analysis.
Results: Higher nevirapine exposure was observed in women carrying the CYP2B6 516G>T polymorphism, but this did not reach statistical significance (P = 0.054). The TGATC CYP2B6 haplotype (g.3003T, 516G, 785A, g.18492T and g.21563C) was associated with increased nevirapine clearance and lower exposure (P = 0.0029). The median time for nevirapine concentrations to reach 10 ng/mL post-partum (nevirapine IC50 for HIV-1) was 14 days [interquartile range (IQR, 14–18)] for TGATC homozygotes, 16 days (14–20) for TGATC heterozygotes and 18 days (14–20) for non-TGATC homozygotes (P = 0.020).
Conclusions: The CYP2B6 516G>T impact on nevirapine concentrations was less pronounced after intra-partum single-dose nevirapine than reported under steady-state conditions, perhaps due to lack of enzyme auto-induction at the time of dosing. Although the TGATC CYP2B6 haplotype may shorten the persistence of nevirapine post-partum, its practical implications for the prevention of HIV transmission or selection of resistance mutations are likely limited.
Keywords: pharmacogenetics , single nucleotide polymorphisms , SNPs