JAC Advance Access published online on February 14, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn029
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Original research |
Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients
1 Department of Internal Medicine, University of Cologne, Köln, Germany 2 Department of Internal Medicine, University of Bonn, Bonn, Germany 3 IPM Study Center, Hamburg/University of Schleswig Holstein, Kiel, Germany 4 PZB, Aachen, Germany 5 Department of Dermatology, St Josef Hospital, Bochum, Germany 6 Department of Internal Medicine, University of Munich, München, Germany 7 Department of Dermatology, University of Essen, Essen, Germany 8 HIV Research and Clinical Care Centre Munich, Munich, Germany 9 Department for Internal Medicine 3, University Hospital Erlangen, University of Erlangen-Nuremberg, Germany 10 Gemeinschaftspraxis Mauss und Kollegen, Düsseldorf, Germany 11 Infectious Diseases Unit, University Medical Center Hamburg Eppendorf, Hamburg, Germany 12 ZKS, Köln, Germany 13 Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zürich, Zürich, Switzerland 14 Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK
Received 27 November 2007; returned 1 January 2008; revised 4 January 2008; accepted 8 January 2008
* Corresponding author. Tel: +44-151-794-5919; Fax: +44-151-794-5656; E-mail: aowen{at}liv.ac.uk
Objectives: The aim of this study was to investigate the frequency of CYP2B6 polymorphisms (according to ethnicity) and the influence of heterozygosity and homozygosity on plasma concentrations of efavirenz and nevirapine.
Methods: Following written informed consent, 225 Caucasians and 146 Blacks were recruited from the German Competence Network for HIV/AIDS. Plasma concentrations of efavirenz and nevirapine were assessed by HPLC, and genotyping for 516G>T, 983T>C and 1459T>C polymorphisms in CYP2B6 was conducted by real-time PCR-based allelic discrimination.
Results: The minor allele frequency for 516G>T, 983T>C and 1459T>C was 0.29, 0 and 0.08 in Caucasians and 0.34, 0.07 and 0.02 in Blacks, respectively. Two Black patients with the 983C allele receiving efavirenz were identified and both were withdrawn from therapy within 1 week of sampling due to toxicity. In multivariate analyses, efavirenz and nevirapine plasma concentrations were significantly associated with 983T>C (P < 0.0001 and P = 0.02, respectively), 516G>T (P < 0.0001 and P = 0.002, respectively) and time of drug analysis post-dose (P < 0.0001 for both). Body mass index was independently related to efavirenz (P = 0.04) but not nevirapine concentrations, and age was related to nevirapine (P = 0.05) but not efavirenz concentrations. Consistent with other studies, 1459C>T was not associated with plasma concentrations of either drug (P > 0.05 for both drugs).
Conclusions: This is the first report that the 983T>C genotype (part of the CYP2B6*18 haplotype) impacts on nevirapine plasma concentrations and the first study to assess the impact of 983C homozygosity on efavirenz concentrations. These data have implications for administration of non-nucleoside reverse transcriptase inhibitors to Black patients.
Key Words: NNRTIs , pharmacogenetics , pharmacokinetics , metabolism , drug disposition
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