Background: Maintaining therapeutic concentrations of antiretrovirals (ARVs) throughout pregnancy is critical to prevent perinatal transmission and maternal resistance development. Physiological changes during pregnancy may alter the pharmacokinetics (PK) of prescribed medicines, particularly those metabolized by cytochrome (CYP) P450 enzymes. To date, no studies have reported etravirine (ETV) PK during pregnancy. ETV is metabolized by and inhibits or induces CYP 3A4, 2C9 and 2C19. The goal was to determine ETV PK parameters during the 2nd and 3rd trimesters compared to the same subjects postpartum and to historical non-pregnant controls.
Methods: P1026s is an ongoing, multi-center, multi-arm, prospective PK study of HIV-1 infected pregnant women on ARVs for routine care. This arm enrolled women on ETV 200 mg twice daily. The PANNA Study is a similar design, enrolling in European countries. Steady-state 12-hour ETV profiles were obtained in the 2nd and 3rd trimesters, and at 4-12 weeks postpartum. Maternal and cord blood samples were collected at delivery. The P1026s target steady-state ETV 12-hour AUC was 2.5 μg*hr/mL (10th percentile in non-pregnant historical controls). The 50th percentile AUC in non-pregnant controls is 4.2 μg*hr/mL, and a suggested minimum concentration from the GRACE trial is 0.16 mg/L. Paired PK parameters were compared with the Wilcoxon signed-rank test at a significance of p<0.05.
Results: Five, 12 and 8 women completed 2nd trimester, 3rd trimester, and postpartum PK evaluations. Median (range) age was 26 (19-43) years. Seven patients were black; 6 Hispanic; and 1 Caucasian. At delivery 9/10 patients had an HIV viral load <50 copies/mL. One subject took ETV 400 mg once daily; her oral clearance (CL/F), AUC0-12, and half-life values are included in the summary data, while individual concentrations were excluded. ETV PK parameters are presented below. The median (range) ratio of cord blood/maternal plasma concentrations (n=5) was 0.59 (0.19-4.25). Six children were HIV uninfected; for five children results are pending.
Conclusions: While 2nd trimester and postpartum ETV PK were similar to non-pregnant adult PK, 3rd trimester exposure was significantly higher than postpartum and historical controls. The metabolism of ETV is complex; pregnancy, ETV itself and other drugs alter the activity of these pathways. The increased 3rd trimester exposure may be due to decreases in CYP2C19 activity and ritonavir exposure. No ETV dose change is needed during pregnancy.