Etravirine Pharmacokinetics in HIV-Infected Pregnant Women

Nikki Mulligan, Stein Schalkwijk, Brookie M Best, Angela Colbers, Jiajia Wang, Edmund V Capparelli, José Moltó, Alice M Stek, Graham Taylor, Elizabeth Smith, Carmen Hidalgo Tenorio, Nahida Chakhtoura, Marjo van Kasteren, Courtney V Fletcher, Mark Mirochnick, David Burger, Nikki Mulligan, Stein Schalkwijk, Brookie M Best, Angela Colbers, Jiajia Wang, Edmund V Capparelli, José Moltó, Alice M Stek, Graham Taylor, Elizabeth Smith, Carmen Hidalgo Tenorio, Nahida Chakhtoura, Marjo van Kasteren, Courtney V Fletcher, Mark Mirochnick, David Burger

Abstract

Background: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women.

Methods: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL).

Results: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0-12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19-4.25) and no perinatal transmission occurred.

Conclusion: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available.

Clinical trial registration: The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929.

Keywords: HIV; etravirine; perinatal transmission; pharmacokinetics; pregnancy.

Figures

Figure 1
Figure 1
IMPAACT subjects are represented in blue and PANNA subjects are represented in green. (A) Paired AUC0–12 data in 2nd trimester, 3rd trimester, and postpartum. (B) Paired C12 data in 2nd trimester, 3rd trimester, and postpartum. (C) Paired CL/F data in 2nd trimester, 3rd trimester, and postpartum.
Figure 2
Figure 2
Median etravirine (ETV) concentration-time curves during the 2nd trimester, 3rd trimester, and postpartum on 200 mg twice-daily dosing. Non-pregnant adult reference line is seen in solid line (Boffito et al., 2007).
Figure 3
Figure 3
(A) Etravirine (ETV) concentration-time curves during the 2nd trimester following 200 mg twice-daily dosing, (B) Etravirine (ETV) concentration-time curves during the 3rd trimester following 200 mg twice-daily dosing, (C) Etravirine (ETV) concentration-time curves postpartum following 200 mg twice-daily dosing.

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