CROI 2016 Abstract eBook
438 Dolutegravir Pharmacokinetics in HIV-Infected Pregnant and PostpartumWomen
Nikki Mulligan 1 ; Brookie M. Best 1 ; Edmund Capparelli 1 ; Alice Stek 2 ; Emily Barr 3 ; Elizabeth Smith 4 ; Nahida Chakhtoura 5 ; JiajiaWang 6 ; Sandra Burchett 7 ; Mark Mirochnick 8 1 Univ of California San Diego, San Diego, CA, USA; 2 Univ of Southern California, Los Angeles, CA, USA; 3 Univ of Colorado Anschutz Med Campus, Aurora, CO, USA; 4 NIAID, NIH, Bethesda, MD, USA; 5 Eunice Kennedy Shriver NICHD, Bethesda, MD, USA; 6 Harvard Sch of PH, Boston, MA, USA; 7 Children’s Hosp Boston, Boston, MA, USA; 8 Boston Univ Sch of Med, Boston, MA, USA Background: Dolutegravir (DTG), an integrase strand transfer inhibitor, is metabolized by UGT1A1 and CYP3A4. It has not been studied in pregnant women or infants. This study described DTG exposure during pregnancy compared to postpartum and in infant washout samples after delivery. Methods: IMPAACT protocol P1026s is an ongoing, nonrandomized, open-label, parallel-group, multi-center phase-IV prospective study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women. Intensive steady-state 24 hour PK profiles of DTG 50 mg once-daily were performed during the 2 nd trimester (2T), 3 rd trimester (3T) and 6-12 weeks postpartum (PP). Infant DTG washout samples were collected if birth weight > 1000 grams and there were no severe malformations or medical conditions. Dolutegravir was measured by validated LC-MS/MS with a quantitation limit of 0.005 mcg/mL. A two-tailed Wilcoxon signed rank test (α = 0.10) was employed for paired within-subject comparison. Results: Thirteen subjects from the United States were enrolled – 9 black, 3 white, 1 American Indian / Alaskan Native with a median 3T age of 32 years (range 22 – 40). DTG PK data were available for 5, 11 and 4 women in 2T, 3T and PP. PK parameters are represented as median (interquartile range) in the table below. AUC 0-24 and C 24h appeared to be lower in the 3T compared to PP, while clearance appeared to be higher, but no significant differences for any PK parameters were found in paired comparisons between 3T and PP (n = 4). Washout DTG PK data were available for 5 infants; elimination half-life was 35 hours (range 32 - 55). Viral load at delivery was < 50 copies/mL for 13 of 13 women (100%). Median infant gestational age at birth was 38.9 weeks. Thirteen of 13 infants were HIV-negative based on best available data. Conclusions: DTG exposure may be lower in pregnancy compared to postpartum. Infant elimination half-life was over twice that of maternal subjects and historical non-pregnant adult controls. More PK, safety and outcome data in pregnant women are needed before DTG can be recommended for clinical use during pregnancy.
439 Rilpivirine Female Genital Tract Concentrations in Pregnant and PostpartumWomen
Mark Mirochnick 1 ; Brookie M. Best 2 ; Angela Kashuba 3 ; Craig Sykes 3 ; Amanda Schauer 3 ; JiajiaWang 4 ; Alice Stek 5 ; Elizabeth Smith 6 ; Nahida Chakhtoura 7 ; Edmund Capparelli 2 1 Boston Univ Sch of Med, Boston, MA, USA; 2 Univ of North California San Diego, San Diego, CA, USA; 3 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4 Harvard Sch of PH, Boston, MA, USA; 5 Univ of Southern California, Los Angeles, CA, USA; 6 NIAID, NIH, Bethesda, MD, USA; 7 Eunice Kennedy Shriver NICHD, Bethesda, MD, USA Background: Genital tract (GT) concentration (conc) of antiretrovirals (ARVs) may play a key role in the success of oral ARVs used for PrEP in HIV uninfected women and for prevention of intrapartumMTCT in HIV infected pregnant women. Female GT conc with chronic oral rilpivirine (RPV) dosing have not previously been described. The impact of pregnancy on RPV ARV secretion into the female GT is unknown. Methods: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Protocol 1026s (P1026s) is an ongoing, multicenter, non-blinded prospective study evaluating the pharmacokinetics of ARVs in pregnant HIV-infected women that included a cohort of pregnant women receiving RPV 25mg once daily as part of clinical care. Plasma (PL) and cervicovaginal fluid (CVF) samples were collected predose and 1, 2 and 4 hours post dose during the 2 nd trimester (2T), 3 rd trimester (3T) and 6-12 weeks postpartum (PP). RPV conc were measured using LC-MS/MS. PL and CVF lower limit of quantitation (LLQ) were 5 and 2 ng/mL, respectively. Area under the conc time curve (AUC) through 4 hours after dosing was estimated using the trapezoidal rule. Pairwise comparisons for PL AUC, CVF AUC and their ratio within each subject between sampling periods were performed using a two- sided Wilcoxon signed rank test with p < 0.05 considered statistically significant. Median (IQR) summary statistics are reported.
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