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Title
Pharmacokinetics of darunavir boosted with cobicistat during pregnancy and postpartum
Presenter
Mark Mirochnick
Authors
J.D. Momper1, B. Best1, J. Wang2, A. Stek3, D.E. Shapiro2, K. George4, E. Barr5, K. Rungruengthanakit6, E. Smith7, N. Chakhtoura8, E.V. Capparelli1, M. Mirochnick9
Institutions
1University of California, San Diego, La Jolla, United States, 2Harvard University, Boston, United States, 3University of Southern California, Los Angeles, United States, 4FHI 360, Durham, United States, 5Children's Hospital Colorado, Aurora, United States, 6Chiang Mai University, Chiang Mai, Thailand, 7National Institute of Allergy and Infectious Diseases, Bethesda, United States, 8National Institute of Child Health and Human Development, Bethesda, United States, 9Boston University, Boston, United States

Background: Darunavir (DRV), an HIV-1 protease inhibitor, is primarily metabolized by CYP3A and must be administered with a pharmacokinetic (PK) booster. The PK of DRV co-administered with ritonavir have been described in pregnancy; however, DRV co-formulated with cobicistat (COBI) has not been studied in pregnant women. This study described DRV exposure when administered in fixed-dose-combination with COBI during pregnancy and postpartum.
Methods: IMPAACT P1026s is an ongoing, nonrandomized, open-label, multi-center study of antiretroviral PK in HIV-infected pregnant women. Steady-state 24-hour PK profiles of DRV following once-daily dosing of 800/150 mg DRV/COBI were performed during the 2nd and 3rd trimesters (2T/3T) and 6-12 weeks postpartum (PP). DRV plasma concentrations were measured by a validated HPLC method. A two-tailed Wilcoxon signed rank test (α = 0.10) was employed for paired within-subject comparison of PK parameters.
Results: Nine subjects from the US were enrolled with a median age of 24 years at delivery (range 17-43). DRV PK data were available for 5, 7, and 6 women in 2T, 3T and PP, respectively. DRV exposure was lower and clearance higher in 3T compared to PP (Table 1). Compared to previously reported values in non-pregnant adults receiving DRV/COBI 800/150 mg once-daily, 24-hour trough DRV concentrations were 78%, 85%, and 61% lower in 2T, 3T, and PP, respectively. Overall, 2/5, 1/7, and 5/6 mothers had AUC0-24 values above the 10th percentile in non-pregnant adult patients at 2T, 3T, and PP, respectively. All subjects had 24-hour trough concentrations above 0.055 ug/mL, the threshold for the average protein binding-adjusted EC50 for wild-type virus. Viral load at delivery was < 50 copies/mL for all women. Median infant gestational age at birth was 37.86 weeks. A patent foramen ovale and ventricular septal defect were reported in one infant and determined possibly treatment related. 7/9 infants were HIV-negative based on best available data, and 2 are indeterminate or pending evaluations.
Conclusions: In women taking DRV in fixed-dose-combination with COBI, the exposure to DRV appeared to be lower in pregnancy compared to postpartum. Additional PK, safety, and outcome data in pregnant women are needed before DRV/COBI can be recommended for use during pregnancy.


Maternal Darunavir Pharmacokinetic Parameters, Median (IQR)
[Maternal Darunavir Pharmacokinetic Parameters, Median (IQR)]

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