title: CYP2B6*6, CYP2B6*18, Body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe.
abstract: BACKGROUND
  Efavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 μg/ml may result in virologic failure and above 4 μg/ml, may result in central nervous system adverse effects. This study used population pharmacokinetics modeling to explore the influence of demographic and pharmacogenetic factors including efavirenz-rifampicin interaction on EFV pharmacokinetics, towards safer dosing of EFV.
  
  
  METHODS
  Patients receiving an EFV-based regimen for their antiretroviral therapy and a rifampicin-containing anti-TB regimen were recruited. EFV plasma concentrations were measured by HPLC and genomic DNA genotyped for variants in the CYP2B6, CYP2A6 and ABCB1 genes. All patients were evaluated for central nervous system adverse effects characterised as sleep disorders, hallucinations and headaches using the WHO ADR grading system. A pharmacokinetic model was built in a forward and reverse procedure using nonlinear mixed effect modeling in NONMEM VI followed by model-based simulations for optimal doses.
  
  
  RESULTS
  CYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance. Patients with the CYP2B6*6TT genotype had a 63% decrease in EFV clearance despite their CYP2B6*18 genotypes with females having 22% higher clearance compared to males. There was a 21% increase in clearance for every 10 kg increase in weight. The effect of TB/HIV co-treatment versus HIV treatment only was not statistically significant. No clinically relevant association between CYP2B6 genotypes and CNS adverse effects was seen, but patients with CNS adverse effects had a 27% lower clearance compared to those without. Model- based simulations indicated that all carriers of CYP2B6*6 TT genotype would be recommended a dose reduction to 200 mg/day, while the majority of extensive metabolisers may be given 400 mg/day and still maintain therapeutic levels.
  
  
  CONCLUSIONS
  This study showed that screening for CYP2B6 functional variants has a high predictability for efavirenz plasma levels and could be used in prescribing optimal and safe EFV doses.
authors.affiliation: Department of Molecular Sciences, African Institute of Biomedical Science and Technology, Dominion House, 211 Herbert Chitepo Street, P.O. Box 2294, Harare, Zimbabwe. milcah_dhoro@yahoo.com.|Department of Clinical Pharmacology, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe. milcah_dhoro@yahoo.com.
authors.forename: Milcah
authors.initials: M
authors.lastname: Dhoro
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa. simba.zvada@gmail.com.
authors.forename: Simbarashe
authors.initials: S
authors.lastname: Zvada
authors.affiliation: Department of Molecular Sciences, African Institute of Biomedical Science and Technology, Dominion House, 211 Herbert Chitepo Street, P.O. Box 2294, Harare, Zimbabwe. bernardngara4@gmail.com.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ngara
authors.affiliation: Department of Clinical Pharmacology, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe. cnhachi@gmail.com.
authors.forename: Charles
authors.initials: C
authors.lastname: Nhachi
authors.affiliation: Department of Medicine, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe. gkadzirange@gmail.com.
authors.forename: Gerald
authors.initials: G
authors.lastname: Kadzirange
authors.affiliation: Department of Harare City Health, Harare, Zimbabwe. pchonzi@hararecity.co.zw.
authors.forename: Prosper
authors.initials: P
authors.lastname: Chonzi
authors.affiliation: Department of Molecular Sciences, African Institute of Biomedical Science and Technology, Dominion House, 211 Herbert Chitepo Street, P.O. Box 2294, Harare, Zimbabwe. collenmasimirembwa@yahoo.com.
authors.forename: Collen
authors.initials: C
authors.lastname: Masimirembwa
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D000480:Alkynes; D000483:Alleles; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D048588:Benzoxazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight; D016022:Case-Control Studies; D003521:Cyclopropanes; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006212:Hallucinations / Q000139:chemically induced; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008954:Models, Biological; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D012727:Sex Characteristics; D012893:Sleep Wake Disorders / Q000139:chemically induced; D014376:Tuberculosis / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D015030:Zimbabwe
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz; D012293:Rifampin