Pharmacokinetic and pharmacogenomic modelling of the CYP3A activity marker 4β-hydroxycholesterol during efavirenz treatment and efavirenz/rifampicin co-treatment

• Verfasst von: Ngaimisi, Eliford [VerfasserIn]
• Verfasst von: Burhenne, Jürgen [VerfasserIn]
• Titel: Pharmacokinetic and pharmacogenomic modelling of the CYP3A activity marker 4β-hydroxycholesterol during efavirenz treatment and efavirenz/rifampicin co-treatment
• Verf.angabe: E. Ngaimisi, O. Minzi, S. Mugusi, P. Sasi, K.-D. Riedel, A. Suda, N. Ueda, M. Bakari, M. Janabi, F. Mugusi, L. Bertilsson, J. Burhenne, E. Aklillu and U. Diczfalusy
• E-Jahr: 2014
• Jahr: 04 August 2014
• Umfang: 9 S.
• Fussnoten: Gesehen am 29.10.2020
• Titel Quelle: Enthalten in: The journal of antimicrobial chemotherapy
• Ort Quelle: Oxford : Oxford Univ. Press, 1975
• Jahr Quelle: 2014
• Band/Heft Quelle: 69(2014), 12, Seite 3311-3319
• ISSN Quelle: 1460-2091
• DOI: doi:10.1093/jac/dku286
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1737373378

Abstract

Objectives: To assess the effect of the major efavirenz metabolizing enzyme (CYP2B6) genotype and the effects of rifampicin co-treatment on induction of CYP3A by efavirenz. Patients and methods: Two study arms (arm 1, n=41 and arm 2, n=21) were recruited into this study. In arm 1, cholesterol and 4β-hydroxycholesterol were measured in HIV treatment-naive patients at baseline and then at 4 and 16 weeks after initiation of efavirenz-based antiretroviral therapy. In arm 2, cholesterol and 4β-hydroxycholesterol were measured among patients taking efavirenz during rifampicin-based tuberculosis (TB) treatment (efavirenz/rifampicin) just before completion of TB treatment and then serially following completion of TB treatment (efavirenz alone). Non-linear mixed-effect modelling was performed. Results: A one-compartment, enzyme turnover model described 4β-hydroxycholesterol kinetics adequately. Efavirenz treatment in arm 1 resulted in 1.74 (relative standard error=15%), 3.3 (relative standard error=33.1%) and 4.0 (relative standard error=37.1%) average fold induction of CYP3A for extensive (CYP2B6*1/*1), intermediate (CYP2B6*1/*6) and slow (CYP2B6*6/*6) efavirenz metabolizers, respectively. The rate constant of 4β-hydroxycholesterol formation [mean (95% CI)] just before completion of TB treatment [efavirenz/rifampicin co-treatment, 7.40×10−7 h−1 (5.5×10−7–1.0×10−6)] was significantly higher than that calculated 8 weeks after completion [efavirenz alone, 4.50×10−7 h−1 (4.40×10−7–4.52×10−7)]. The CYP3A induction dropped to 62% of its maximum by week 8 of completion. Conclusions: Our results indicate that efavirenz induction of CYP3A is influenced by CYP2B6 genetic polymorphisms and that efavirenz/rifampicin co-treatment results in higher induction than efavirenz alone.