Prenatal efavirenz exposure is independently associated with maternal, but not fetal CYP2B6 genotype

Abstract

Objectives Understanding the influence of fetal and maternal genetics on prenatal drug exposure could potentially improve benefit-risk evaluation. In this study, we investigated the impact of two functional polymorphisms in CYP2B6 on prenatal exposure to efavirenz. Methods Dried blood spot (DBS) samples were collected from HIV-positive pregnant women (n = 112) and their newborns (n = 107) at delivery. They were genotyped for single nucleotide polymorphisms in CYP2B6. Efavirenz was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results Significant correlations were observed in efavirenz concentration between maternal and newborn (r = 0.46, R 2 = 0.21, P < 0.001), and maternal and cord (r = 0.83, R 2 = 0.68, P < 0.001) samples. Median (interquartile range) newborn plasma-to-maternal plasma and cord-to-maternal plasma ratios were 0.85 (0.03–3.49) and 0.78 (0.23–1.96), respectively. Newborn efavirenz concentration in DBS varied significantly based on composite maternal CYP2B6 genotype: fast (CYP2B6 516GG and 983TT, n = 26), 747 ng/ml (602–1060); intermediate (CYP2B6 516GT or 983TC n = 50), 1177 ng/ml (898–1765); and slow (CYP2B6 516GT and 983TC or 516TT or 983CC, n = 14), 3094 ng/ml (2126–3812). Composite newborn CYP2B6 genotype was, however, not significantly associated with prenatal exposure. Efavirenz concentration in newborn stratified as fast (n = 25), intermediate (n = 36), and slow metabolizers (n = 19) from prenatal exposure was 999.7 (774–1285), 1240 (709–1984), and 1792 ng/ml (1201–3188), respectively. Conclusion The clinical relevance of the observed influence of maternal genetics on prenatal efavirenz exposure requires further investigation.