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Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients

Abstract

We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4β-hydroxycholesterol/cholesterol (4β-OHC/Chol) as a marker for CYP3A induction. Plasma 4β-hydroxycholesterol and cholesterol concentrations were determined at baseline, and at the 4th, 16th and 48th week of efavirenz-based highly active antiretroviral therapy in antiretroviral therapy-naive HIV patients (n=77). Efavirenz plasma concentrations were quantified at weeks 4 and 16. CYP2B6, CYP3A5, ABCB1, UGT2B7 genotyping were done. Compared with baseline, the median plasma 4β-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4β-OHC/Chol ratio at weeks 16 (P=0.02) and 48 (P=0.04) being highest in CYP2B6*6/*6>*1/*6>*1/*1. There were positive correlations between plasma efavirenz and 4β-OHC/Chol ratios (week 4: P=0.02, week 16: P=0.001). CYP3A enzyme induction by efavirenz is pronounced in CYP2B6 slow metabolizers who have high efavirenz plasma exposure.

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Acknowledgements

We are grateful to study participants and Lilleba Bohman for dedicated technical assistance. This study is supported by grant from European and Developing Countries Clinical Trial Partnership (grant no. CT.2005.32030.001), Swedish research council (grant no. VR 3902, 348-2011-7383), the Swedish International Development Cooperation Agency SIDA (grant no. SWE 2004–098, HIV-2006-031, SWE 2007–270) and Karolinska Institutet.

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Correspondence to E Aklillu.

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Habtewold, A., Amogne, W., Makonnen, E. et al. Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients. Pharmacogenomics J 13, 484–489 (2013). https://doi.org/10.1038/tpj.2012.46

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