title: The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children.
abstract: Using a model-based approach, the efavirenz steady-state pharmacokinetics in African children is characterized, quantifying demographic and genotypic effects on the drug's disposition. Simulations are also conducted allowing prediction of optimized doses of efavirenz in this population.
  
  
  
  We modelled the steady-state population pharmacokinetics of efavirenz in Ugandan and Zambian children using nonlinear mixed-effects modelling. Individual mid-dose efavirenz concentrations were derived and simulations explored genotype-based dose optimization strategies.
  
  
  
  A two-compartment model with absorption through transit compartments well described 2086 concentration-time points in 169 children. The combined effect of single nucleotide polymorphisms (SNPs) 516G>T and 983T>C explained 44.5% and 14.7% of the variability in efavirenz clearance and bioavailability, respectively. The detected frequencies of composite CYP2B6 genotype were 0.33 for 516GG|983TT, 0.35 for 516GT|983TT, 0.06 for 516GG|983TC, 0.18 for 516TT|983TT, 0.07 516GT|983TC and 0.01 for 516GG|983CC. The corresponding estimated clearance rates were 6.94, 4.90, 3.93, 1.92, 1.36, and 0.74 l h(-1) for a 15.4 kg child and median (95% CI) observed mid-dose concentrations 1.55 (0.51-2.94), 2.20 (0.97-4.40), 2.03 (1.19-4.53), 7.55 (2.40-14.74), 7.79 (3.66-24.59) and 18.22 (11.84-22.76) mg l(-1) , respectively. Simulations showed that wild-type individuals had exposures at the bottom of therapeutic range, while slower metabolizers were overexposed.
  
  
  
  Dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bienczak
authors.affiliation: MRC Clinical Trials Unit at University College London, London, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Cook
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Adeniyi
authors.initials: A
authors.lastname: Olagunju
authors.affiliation: University Teaching Hospital, Department of Paediatrics and Child Health, Lusaka, Zambia.
authors.forename: Veronica
authors.initials: V
authors.lastname: Mulenga
authors.affiliation: Joint Clinical Research Centre, Kampala, Uganda.
authors.forename: Cissy
authors.initials: C
authors.lastname: Kityo
authors.affiliation: Baylor College of Medicine Bristol Myers Squibb Children's Clinical Centre of Excellence, Kampala, Uganda / Gulu Regional Centre of Excellence, Gulu, Uganda.
authors.forename: Addy
authors.initials: A
authors.lastname: Kekitiinwa
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.affiliation: MRC Clinical Trials Unit at University College London, London, UK.
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.affiliation: MRC Clinical Trials Unit at University College London, London, UK.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Burger
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
mesh_terms: D000293:Adolescent; D000480:Alkynes; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044383:Black People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D020641:Polymorphism, Single Nucleotide; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D014454:Uganda; D015024:Zambia
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz
keywords: Africa; CYP2B6; children; efavirenz; pharmacogenetics