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Pharmacokinetics of Rilpivirine in HIV-Infected Women During Pregnancy and Postpartum
Mark Mirochnick1, Brookie M. Best2, Alice Stek3, Regis Kreitchmann8, Jiajia Wang4, David Shapiro4, Elizabeth Smith5, Lynne Mofenson6, Tim R. Cressey7, Edmund Capparelli2
1 Boston University School of Medicine, Hingham, MA, United States. 2 University of California San Diego, San Diego, CA, United States. 3 University of Southern California, Los Angeles, CA, United States. 4 Harvard School of Public Health, Boston, MA, United States. 5 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, United States. 6 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, United States. 7 Harvard School of Public Health/Chiang Mai University, Chang Mai, Thailand. 8 Irmandade da Santa Casa de Misericordia de Porto Alegre, Porte Alegre, Brazil.
Background: Rilpivirine (RPV), a 2nd generation non-nucleoside reverse transcriptase inhibitor, has increased absorption when taken with food and is primarily metabolized by cytochrome P450 3A4. During pregnancy, physiological changes including alterations in intestinal transit time and increased CYP 3A4 activity may impact systemic drug exposure. The impact of pregnancy on RPV pharmacokinetics (PK) is unknown.
Methods: IMPAACT Protocol P1026s is an ongoing, multicenter, non-blinded prospective study evaluating the PK of antiretrovirals (ARV) in pregnant HIV-infected women that included a cohort of US pregnant women receiving as part of clinical care combination ARV regimens including RPV 25 mg once daily with food. Intensive steady-state 24 hour PK profiles were performed during the 2nd trimester, 3rd trimester and 6-12 weeks postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma RPV concentrations were measured using liquid chromatography-mass spectrometry, with a lower limit of quantitation of 0.010 mcg/mL. The minimum target for RPV AUC24 was 0.88 mcg*hr/mL, the 10th percentile AUC for non-pregnant adults. Pairwise comparisons within each subject between time points were performed using a two-sided Wilcoxon signed rank test.
Results: RPV PK data were available for 26 women. PK parameters are presented in the table below as median (range). There were no significant differences in any PK parameters for the 2nd or 3rd trimester compared to postpartum. Mean (90% CI) for the ratio of 2nd or 3rd trimester to postpartum log-transformed pk parameters were 1.05 (0.78-1.32) and 1.01 (0.77-1.24) for AUC and 0.94 (0.69-1.18) and 0.91 (0.70-1.12) for C(24)h, respectively. Median (range) RPV concentrations (mcg/mL) in cord blood and maternal delivery samples, and their ratio were 0.054 (BQL (below quantitation limit) - 0.102), 0.103 (BQL – 0.234) and 0.53 (0.38 – 0.83). RPV was well tolerated by all study mothers. Viral load at delivery was below 400 copies/mL for 22 of 24 women and below 50 copies/mL for 17 of 24. No infants were HIV infected, but infection data through the final 24 week visit are only available for 7 infants.
Conclusions: No significant differences in RPV exposure during pregnancy and postpartum were observed. The standard RPV dose provides adequate RPV exposure during pregnancy.