Pharmacogenetics of Efavirenz Exposure in Cervicovaginal Fluid during Pregnancy and Postpartum

Abstract

In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy. Women receiving efavirenz‐containing antiretroviral therapy were recruited from two hospitals in Nigeria during 2017–2020. Sparse CVF and plasma samples were obtained during pregnancy to assess the possible association between drug concentration and CYP2B6 polymorphisms (stage I). Participants were stratified into three CYP2B6 516G>T (rs3745274) genotype groups and re‐enrolled for intensive pharmacokinetic sampling (stage II). Overall, 159 women (142 pregnant and 12 postpartum) contributed samples in stage I (88 CVF, 81 plasma and 73 paired). CYP2B6 516G>T (rs3745274) remained independently associated with log10 efavirenz CVF concentration during pregnancy after adjusting for plasma concentration, with β (Log10 efavirenz concentration, 95%CI) of 0.204 (0.027, 0.382), P = 0.025). Median (IQR) efavirenz Cmin in CVF during pregnancy (n = 12) vs. postpartum (n = 12) was 243 ng/mL (168–402) vs. 447 ng/mL (159–974), Cmax was 1,031 ng/mL (595–1,771) vs. 1,618 ng/mL (675–2,695), and AUC0‐24h was 16,465 ng.h/mL (9,356–30,417) vs. 30,715 ng.h/mL (10,980–43,714). CVF‐to‐plasma AUC ratio was 0.36 during pregnancy and 0.46 postpartum. Upon stratification, efavirenz clearance during pregnancy was 57.9% higher than postpartum in patients with the CYP2B6 516GT genotype; the AUC0‐24h and Cmax were 33.8% and 8.6% lower, respectively. Efavirenz Cmin in CVF exceeded the protein binding‐adjusted IC90 (PBIC90) of 126 ng/mL during pregnancy and postpartum. Efavirenz is well distributed into the CVF; both pregnancy and CYP2B6 polymorphisms affect the extent of exposure.