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.

High CYP2A6 Enzyme Activity as Measured by a Caffeine Test and Unique Distribution of CYP2A6 Variant Alleles in Ethiopian Population

“…The importance of CYP2A6 di Iulio et al, 2009;Kwara et al, 2009) and CYP3A5 metabolic pathways (Habtewold et al, 2011) for efavirenz disposition, particularly in CYP2B6 slow metabolizers, has been reported. Thus, we here found higher CYP2A6 enzyme activity in Ethiopians and have previously reported higher total CYP3A activity and unique distribution of CYP3A5 genotype in Ethiopians than in Tanzanians (Gebeyehu et al, 2011;Habtewold et al, 2013). Apparently the high CYP2A6 and CYP3A enzyme activity in Ethiopians may salvage the CYP2B6-mediated slow metabolism among patients carrying defective CYP2B6 variant alleles.…”

Serum Levels of 25-Hydroxyvitamin D and the CYP3A Biomarker 4β-Hydroxycholesterol in a High-Dose Vitamin D Supplementation Study

“…There were significantly lower 4b-hydroxycholesterol levels in men than in women (P , 0.05). dmd.aspetjournals.org in studies on CYP3A induction (Kanebratt et al, 2008;Wide et al, 2008;Habtewold et al, 2012), showing good concordance with the response in other markers of CYP3A activity such as quinine metabolic ratio (Kanebratt et al, 2008) or the 6b-hydroxycortisol-to-cortisol ratio in urine (Mårde Arrhen et al, 2012). CYP3A4 expression is regulated by a complex network of transcription factors, e.g., the (VDR), pregnane X receptor, and constitutive androstane receptor (Drocourt et al, 2002).…”

Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects

“…After switching from efavirenz treatment to doravirine treatment, as anticipated, the doravirine PK were reduced as a result of persisting efavirenz-mediated CYP3A4 induction. In HIV-infected patients, the inductive effect of efavirenz on CYP3A4, assessed by measuring the percent increase in the plasma 4␤-hydroxycholesterol/cholesterol ratio (4␤-OHC/cholesterol) from that at the baseline, appears to be near maximal at 4 weeks, with only a slight increase being seen after 16 weeks (14). The observed increases in the 4␤-OHC/cholesterol ratio for weeks 4 and 16 were 257% and 291%, respectively (14).…”

“…In HIV-infected patients, the inductive effect of efavirenz on CYP3A4, assessed by measuring the percent increase in the plasma 4␤-hydroxycholesterol/cholesterol ratio (4␤-OHC/cholesterol) from that at the baseline, appears to be near maximal at 4 weeks, with only a slight increase being seen after 16 weeks (14). The observed increases in the 4␤-OHC/cholesterol ratio for weeks 4 and 16 were 257% and 291%, respectively (14). However, as steady-state efavirenz concentrations are attained in approximately 14 days, nearly maximal induction is anticipated as early as 2 weeks after dosing starts.…”