Dataset Information

The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children.

ABSTRACT: AIMS: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. METHODS: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. RESULTS: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. CONCLUSIONS:Dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C.

SUBMITTER: Bienczak A

PROVIDER: S-EPMC4917805 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children.

Bienczak Andrzej A Cook Adrian A Wiesner Lubbe L Olagunju Adeniyi A Mulenga Veronica V Kityo Cissy C Kekitiinwa Addy A Owen Andrew A Walker A Sarah AS Gibb Diana M DM McIlleron Helen H Burger David D Denti Paolo P

British journal of clinical pharmacology 20160425 1

<h4>Aims</h4>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.<h4>Methods</h4>We modelled the steady-state population pharmacokinetics of efavirenz in Ugandan and Zambian children using nonlinear mixed-effects modelling. Individual mid-dose efavirenz concentrati ...[more]

PMID: 26991336

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Project description:BackgroundLimited data exist on efavirenz pharmacokinetics in HIV-positive pregnant women and neonatal washout.MethodsHIV-infected pregnant women receiving 600 mg efavirenz once daily had intensive steady-state 24-h pharmacokinetics profiles during the second trimester (2T), third trimester (3T) and 6-12 weeks postpartum (PP). Maternal and umbilical cord blood samples were drawn at delivery and neonatal washout pharmacokinetics were determined. Therapeutic targets were the estimated 10th percentile efavirenz area under the concentration-time curve (AUC) in non-pregnant historical controls (40.0 μg•h/ml) and a trough concentration (C24 h) of 1 μg/ml. Data were prospectively collected within two trials: IMPAACT P1026s (United States) and PANNA (Europe).ResultsAmong 42 women studied, 15, 42 and 40 had efavirenz pharmacokinetic data available in 2T, 3T and PP, respectively. Median (range) 3T age 33 (20.7-43.5) years, weight 74 (50-132) kg and gestational age 33.4 (28.4-37.9 weeks). Efavirenz AUC during the 3T (60 μg•h/ml) was similar to that reported in non-pregnant adults (58 μg•h/ml). Exposure in the 2T was lower, but within the 0.80-1.25 range. C24 concentrations during pregnancy were lower compared to historical controls on 600 mg efavirenz, however, they were similar to the C24 concentrations after equally potent dose of 400 mg efavirenz. Cord blood/maternal plasma concentration ratio (range) was 0.67 (0.36-0.95). Among 23 infants with washout data available, median (interquartile range) elimination half-life was 65.6 h (40.6-129). HIV RNA viral loads at delivery were <400 and <50 copies/ml for 96.7% and 86.7% of women, respectively. In 3T and PP, respectively, 8/41 (19%) and 6/40 (15%) had AUC below target; 7/41 (17%) and 3/39 (8%) had C24 below target.ConclusionsEfavirenz exposure was similar during pregnancy compared with PP, C24 was in line with C24 after 400 mg equipotent efavirenz dosing. Efavirenz readily crossed the placenta and infant elimination half-life was over twice that of maternal participants. Clincaltrials.gov identifiers: NCT00825929 and NCT00042289.

Project description:Efavirenz-based combination antiretroviral-therapy (cART) is the recommended regimen during tuberculosis (TB) therapy. In a multi-national parallel prospective-cohort study, we investigated the impact of population and pharmacogenetic variations for efavirenz pharmacokinetics, auto-induction, and immunologic outcome during antituberculosis treatment. A total of 921 treatment-naïve HIV patients with (196 Ethiopians and 231 Tanzanians) or without TB co-infection (285 Ethiopians and 209 Tanzanians) were enrolled and treated with efavirenz-based cART. TB-HIV patients started rifampicin-based anti-TB therapy 4 weeks before cART. Efavirenz plasma concentrations were measured on the 4th and 16th weeks of cART. Genotyping for CYP2B6, CYP3A5, ABCB1, UGT2B7, and SLCO1B1 was done. CD4 cells-count was measured at baseline, 12th, 24th, and 48th weeks of cART. Among HIV-only cohort, plasma efavirenz concentration and median CD4 cell count were significantly higher in Tanzanians than Ethiopians, and both CYP2B6 genotype and population-variation were significant predictors of efavirenz plasma concentration. Within-population analyses indicated a pronounced efavirenz autoinduction in Tanzanians as reflected by a significant decrease of plasma efavirenz concentration over time (p = 0.0001), but not in Ethiopians. Among TB-HIV cohort, there were no significant between-population differences in plasma efavirenz concentrations or CD4 cell-recovery, and CYP2B6 genotype but not population-variation was a significant predictor of efavirenz plasma exposure. In Tanzanian patients, short-term anti-TB co-treatment significantly reduced the mean plasma efavirenz concentration in CYP2B6*1/*1 genotype at week-4 (p = 0.005), but not at week-16 of cART. In Ethiopian patients, anti-TB cotreatment increased the mean plasma efavirenz concentration among CYP2B6*6 carriers at week-4 (p = 0.003) and week-16 (p = 0.035) of cART. In general, long-term anti-TB co-treatment increased plasma efavirenz concentration at week 16 of cART in both Ethiopians and Tanzanians being higher in CYP2B6*6/*6 > *1/*6 > *1/*1 genotypes. In TB-HIV patients, baseline body mass index (BMI), viral load, and WHO clinical-stage but not genotype, population-variation, or efavirenz concentration were significant predictors of immunologic outcome at week-48. In summary efavirenz auto-induction, pharmacokinetics, and the immunologic outcome are influenced by population-variation, anti-TB co-medication, and CYP2B6 genotype. CYP2B6 genotype is a significant predictor of efavirenz plasma exposure regardless of population-variation or antituberculosis co-treatment, but population-variation is insignificant during antituberculosis treatment. CYP2B6 genotype, population, and geographic differences need to be considered for efavirenz dosage-optimization.

Dataset Information

The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children.

Publications

The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children.

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