Bienczak, A;
Cook, A;
Wiesner, L;
Olagunju, A;
Mulenga, V;
Kityo, C;
Kekitiinwa, A;
... Denti, P; + view all
(2016)
The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children.
British Journal of Clinical Pharmacology
, 82
(1)
pp. 185-198.
10.1111/bcp.12934.
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Abstract
AIM: To characterise the efavirenz steady-state pharmacokinetics in African children using model-based approach, quantifying demographic and genotypic effects on the drug's disposition, and conduct simulations allowing prediction of optimised 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 optimisation strategies. RESULTS: A 2-compartment model with absorption through transit compartments well described 2086 concentration-time points in 169 children. The combined effect of SNPs 516GT and 983TC 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 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, respectively. Simulations showed that wild-type individuals had exposures at the bottom of therapeutic range, while slower metabolisers were over-exposed. CONCLUSIONS: Dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G > T and 983 T > C.
| Type: | Article |
|---|---|
| Title: | The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bcp.12934 |
| Publisher version: | http://dx.doi.org/10.1111/bcp.12934 |
| Language: | English |
| Additional information: | © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Africa, CYP2B6, children, efavirenz, pharmacogenetics |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1483154 |
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