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Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients

Wyen, Christoph ; Hendra, Heidy ; Vogel, Martin ; Hoffmann, Christian ; Knechten, Heribert ; Brockmeyer, Norbert H. ; Bogner, Johannes R. ; Rockstroh, Jürgen ; Esser, Stefan ; Jaeger, Hans ; Harrer, Thomas ; Mauss, Stefan ; van Lunzen, Jan ; Skoetz, Nicole ; Jetter, Alexander ; Groneuer, Christiane ; Fätkenheuer, Gerd ; Khoo, Saye H. ; Egan, Deirdre ; Back, David J. ; Owen, Andrew

In: Journal of Antimicrobial Chemotherapy, 2008, vol. 61, no. 4, p. 914-918

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    Title
    • Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients
    Author
    • Wyen, Christoph. Department of Internal Medicine, University of Cologne, Köln, Germany
    • Hendra, Heidy. Department of Internal Medicine, University of Cologne, Köln, Germany
    • Vogel, Martin. Department of Internal Medicine, University of Bonn, Bonn, Germany
    • Hoffmann, Christian. IPM Study Center, Hamburg/University of Schleswig Holstein, Kiel, Germany
    • Knechten, Heribert. PZB, Aachen, Germany
    • Brockmeyer, Norbert H.. Department of Dermatology, St Josef Hospital, Bochum, Germany
    • Bogner, Johannes R.. Department of Internal Medicine, University of Munich, München, Germany
    • Rockstroh, Jürgen. Department of Internal Medicine, University of Bonn, Bonn, Germany
    • Esser, Stefan. Department of Dermatology, University of Essen, Essen, Germany
    • Jaeger, Hans. HIV Research and Clinical Care Centre Munich, Munich, Germany
    • Harrer, Thomas. Department for Internal Medicine 3, University Hospital Erlangen, University of Erlangen-Nuremberg, Germany
    • Mauss, Stefan. Gemeinschaftspraxis Mauss und Kollegen, Düsseldorf, Germany
    • van Lunzen, Jan. Infectious Diseases Unit, University Medical Center Hamburg Eppendorf, Hamburg, Germany
    • Skoetz, Nicole. ZKS, Köln, Germany
    • Jetter, Alexander. Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zürich, Zürich, Switzerland
    • Groneuer, Christiane. Department of Internal Medicine, University of Cologne, Köln, Germany
    • Fätkenheuer, Gerd. Department of Internal Medicine, University of Cologne, Köln, Germany
    • Khoo, Saye H.. Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK
    • Egan, Deirdre. Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK
    • Back, David J.. Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK
    • Owen, Andrew. Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Journal of Antimicrobial Chemotherapy, 2008, vol. 61, no. 4, p. 914-918. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:304653
    Summary
    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