title: Effect of diurnal variation, CYP2B6 genotype and age on the pharmacokinetics of nevirapine in African children.
abstract: To characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children.
  
  
  
  Non-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration-time data from 414 children aged 0.3-15 years.
  
  
  
  Nevirapine pharmacokinetics was best described using a one-compartment disposition model with elimination through a well-stirred liver model accounting for a first-pass effect and transit-compartment absorption. Intrinsic clearance was affected by diurnal variation (characterized using a cosine function with peak amplitude 29% at 12 noon) and CYP2B6 metabolizer status [extensive metabolizer (EM) 516GG|983TT, reference; intermediate metabolizer (IM) 516GT|983TT or 516GG|983TC, 17% lower; slow metabolizer (SM) 516TT|983TT or 516GT|983TC, 50% lower; ultra-slow metabolizer (USM) 516GG|983CC, 68% lower]. Age was found to affect pre-hepatic bioavailability: 31.7% lower at birth and increasing exponentially. Median (90% CI) evening Cminvalues in the different metabolizer groups were 5.01 (3.01-7.47), 6.55 (3.65-13.32), 11.59 (5.44-22.71) and 12.32 (12.32-27.25) mg/L, respectively. Evening Cminvalues were <3 mg/L in 43% of EM weighing <6 kg and 26% of IM weighing <6 kg, while 73% of SM and 88% of USM in all weight-bands had evening Cminvalues >8 mg/L. Cminwas not markedly affected by administration time, but was altered by unequal splitting of the daily dose.
  
  
  
  Diurnal variation does not greatly affect nevirapine exposure. However, when daily doses cannot be split equally, the larger dose should be given in the morning. To achieve homogeneous exposures, nevirapine doses for SM and USM should be reduced by 50%, and children weighing <6 kg with EM or IM metabolizer status should receive the same dose as children weighing 6-10 kg.
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 Paediatrics and Child Health, University Teaching Hospital, 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: MRC Clinical Trials Unit at University College London, London, UK.
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
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: Diana M
authors.initials: DM
authors.lastname: Gibb
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: Helen
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa paolo.denti@uct.ac.za.
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
mesh_terms: D000293:Adolescent; D000349:Africa; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002940:Circadian Rhythm; D015331:Cohort Studies; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D019829:Nevirapine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6