The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children
| Autor: | Paolo Denti, Helen McIlleron, Cissy Kityo, Adrian Cook, Adeniyi Olagunju, Andrew Owen, David M. Burger, Lubbe Wiesner, Veronica Mulenga, Andrzej Bienczak, Addy Kekitiinwa, A. Sarah Walker, Diana M. Gibb |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pharmacology Oncology medicine.medical_specialty education.field_of_study Efavirenz business.industry 030106 microbiology Population Single-nucleotide polymorphism Bioavailability 03 medical and health sciences chemistry.chemical_compound chemistry Pharmacokinetics Internal medicine Genotype medicine Pharmacology (medical) business education Cytochrome P-450 CYP2B6 Pharmacogenetics |
| Zdroj: | British Journal of Clinical Pharmacology. 82:185-198 |
| ISSN: | 0306-5251 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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