Journal article
The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children
- Abstract:
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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 983T>C.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.0MB, Terms of use)
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- Publisher copy:
- 10.1111/bcp.12934
Authors
- Grant:
- IP.2007.33011.006
- Publisher:
- Wiley
- Journal:
- British Journal of Clinical Pharmacology More from this journal
- Publication date:
- 2016-03-01
- Acceptance date:
- 2016-03-10
- DOI:
- ISSN:
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1365-2125
- Keywords:
- Pubs id:
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pubs:611144
- UUID:
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uuid:0bcf11f8-e015-4110-8254-d21a37dc39a7
- Local pid:
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pubs:611144
- Source identifiers:
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611144
- Deposit date:
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2016-03-19
- ARK identifier:
Terms of use
- Copyright holder:
- Walker et al
- Copyright date:
- 2016
- Notes:
- © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley and Sons Ltd on behalf of The British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
- Licence:
- CC Attribution (CC BY)
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