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J Antimicrob Chemother. 2014 Dec;69(12):3311-9. doi: 10.1093/jac/dku286. Epub 2014 Aug 4.

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

Author information

1
Department of Pharmacognosy, Unit of Pharmacology and Therapeutics, School of Pharmacy, Muhimbili University of Health and Allied Sciences, PO Box 65013, Dar es Salaam, Tanzania Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden engaimisi@gmail.com.
2
Department of Pharmacognosy, Unit of Pharmacology and Therapeutics, School of Pharmacy, Muhimbili University of Health and Allied Sciences, PO Box 65013, Dar es Salaam, Tanzania.
3
Department of Clinical Pharmacology, School of Medicine, Muhimbili University of Health and Allied Sciences, PO Box 65001, Dar es Salaam, Tanzania.
4
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
5
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden.
6
Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, PO Box 65001, Dar es Salaam, Tanzania.
7
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, C1: 74, SE-141 86 Stockholm, Sweden.

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.

KEYWORDS:

HIV; induction; pharmacogenetics

PMID:
25096076
DOI:
10.1093/jac/dku286
[Indexed for MEDLINE]

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