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


Bienczak, Andrzej, Cook, Adrian, Wiesner, Lubbe, Olagunju, Adeniyi ORCID: 0000-0002-6588-5749, Mulenga, Veronica, Kityo, Cissy, Kekitiinwa, Addy, Owen, Andrew ORCID: 0000-0002-9819-7651, Walker, A Sarah, Gibb, DianaM et al (show 3 more authors) (2016) The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 82 (1). pp. 185-198.

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Abstract

<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 concentrations were derived and simulations explored genotype-based dose optimization strategies.<h4>Results</h4>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.<h4>Conclusions</h4>Dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C.

Item Type: Article
Uncontrolled Keywords: Africa, children, CYP2B6, efavirenz, pharmacogenetics
Depositing User: Symplectic Admin
Date Deposited: 13 Nov 2017 16:04
Last Modified: 19 Jan 2023 06:50
DOI: 10.1111/bcp.12934
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3012062
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