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Pharmacokinetics of Etravirine in HIV-1–Infected Pregnant Women
M Ramgopal1, O Osiyemi2, C Zorrilla3, HM Crauwels4, R Ryan5, K Brown6, V Hillewaert7, B Baugh6
1 Midway Immunology and Research Center, Fort Pierce, FL, United States. 2 Triple O Research Institute PA, West Palm Beach, FL, United States. 3 University of Puerto Rico School of Medicine, San Juan, PR, United States. 4 Janssen Infectious Diseases, Beerse, Belgium. 5 Janssen Research & Development, Titusville, NJ, United States. 6 Janssen Therapeutics, Titusville, NJ, United States. 7 Janssen Research & Development, Beerse, Belgium.
Background: Antiretroviral (ARV) therapy during pregnancy has dramatically reduced the risk of mother-to-child transmission. Physiologic changes during pregnancy can affect the PK of ARVs.
Methods: Phase IIIb study evaluating HIV-1–infected pregnant women (age ≥18 years), in the 2nd trimester of pregnancy, receiving ETR 200mg bid with other ARVs. ETR plasma concentrations were assessed predose and 1, 2, 3, 4, 6, 9 and 12 hours postdose during the 2nd and 3rd trimesters and (6-12 weeks) postpartum. ETR PK parameters were derived using non-compartmental analysis. Safety and efficacy were investigated at each visit and summarized using descriptive statistics.
Results: Fifteen women (11 black, 2 Hispanic, 2 white) were enrolled; 13 had evaluable PK. ETR AUC24h, Cmin and Cmax were higher by 46% (LS Means ratio, 90% CI: 1.46, 1.12-1.90), 131% (2.31, 1.26-4.22) and 39% (1.39, 1.15-1.67) during the 2nd trimester and by 28% (1.28, 0.98-1.69), 93% (1.93, 1.03-3.61) and 31% (1.31, 1.08-1.59) during the 3rd trimester, versus postpartum. ETR post-partum PK was comparable to historic controls in HIV-1 infected subjects (DUET). Though mean ETR exposures during pregnancy were higher compared to post-partum, the observed exposures were still in range with those previously observed in HIV-1 infected subjects treated with ETR 200 mg bid. Unbound ETR PK will be explored. Median baseline (BL) viral load (VL) was 49 copies/mL; for one woman, BL VL was 54,000 copies/mL and remained detectable throughout the study. All other women had VL<400 copies/mL during pregnancy (>90% had VL<50 copies/mL). The median increases in CD4 from baseline were 29 and 45 cells/mm3 for the 2nd and 3rd trimester respectively, and were >100 cells/mm3 postpartum. Four subjects had serious adverse events (SAEs), none of which were at least possibly related to ETR (premature rupture of membranes; hypertension; headache; and one subject had 3 SAEs: pregnancy induced hypertension [twice] and premature labor). One subject had a treatment emergent adverse event (atopic dermatitis) that was at least possibly related to study drug. All infants were HIV-negative.
Conclusions: ETR exposure increased during pregnancy; this was not associated with an increased occurrence of SAEs. The regimen was well tolerated. Virologic response was maintained throughout the study and there was no mother-to-child transmission. These data indicate ETR 200 mg bid could be a treatment option for HIV-1 infected pregnant women.