title: Pharmacokinetic and pharmacogenomic modelling of the CYP3A activity marker 4β-hydroxycholesterol during efavirenz treatment and efavirenz/rifampicin co-treatment.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 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.
authors.forename: E
authors.initials: E
authors.lastname: Ngaimisi
authors.affiliation: 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.
authors.forename: O
authors.initials: O
authors.lastname: Minzi
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Muhimbili University of Health and Allied Sciences, PO Box 65001, Dar es Salaam, Tanzania.
authors.forename: S
authors.initials: S
authors.lastname: Mugusi
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Muhimbili University of Health and Allied Sciences, PO Box 65001, Dar es Salaam, Tanzania.
authors.forename: P
authors.initials: P
authors.lastname: Sasi
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: K-D
authors.initials: KD
authors.lastname: Riedel
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Suda
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, PO Box 65001, Dar es Salaam, Tanzania.
authors.forename: M
authors.initials: M
authors.lastname: Bakari
authors.affiliation: Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, PO Box 65001, Dar es Salaam, Tanzania.
authors.forename: M
authors.initials: M
authors.lastname: Janabi
authors.affiliation: Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, PO Box 65001, Dar es Salaam, Tanzania.
authors.forename: F
authors.initials: F
authors.lastname: Mugusi
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Bertilsson
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Burhenne
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Aklillu
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, C1: 74, SE-141 86 Stockholm, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Diczfalusy
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D048588:Benzoxazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D006888:Hydroxycholesterols / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D006888:Hydroxycholesterols; C099828:cholest-5-ene-3,4-diol; C104464:CYP3A protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz; D012293:Rifampin
keywords: HIV; induction; pharmacogenetics