CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

1016 Modeling Tail-Phase PK From Early Pregnancy to Postpartum and Fetal Exposure to Long-Acting CAB-RPV Shakir Atoyebi, Catriona Waitt, Adeniyi Olagunju University of Liverpool, Liverpool, UK Background: Long-acting cabotegravir and rilpivirine combination (CAB-RPV LA) is approved for HIV treatment in adults. However, individuals who become pregnant might prefer to discontinue it due to lack of definitive data on safety. The aim of this study was to estimate fetal exposure to CAB-RPV LA and time to subtherapeutic plasma level if discontinued early in pregnancy. Methods: Adult and pregnancy physiologically based pharmacokinetic (PBPK) models were used which had been previously validated for the disposition of LA CAB and LA RPV including tail-phase PK data from published studies. Approved monthly adult dosing of LA CAB-RPV was initiated in a virtual population of non-pregnant women until steady state. We simulated discontinuation at steady state after only one injection during pregnancy. Fetal exposure to both drugs in the second and third trimesters was estimated. Tail-phase PK of CAB and RPV from LA injections was characterised during gestation and until 6 months postpartum. Results: A total of 8 scenarios were simulated (n = 100 each) in virtual populations of non-pregnant, pregnant and postpartum women. Mean (SD) age was 27 (5) yrs and body weight was 58 (13) kg. PK tail was driven by residual drug in muscle depot and was predicted to stabilise at steady state. Predicted median (IQR) maternal plasma concentration was 478 (436-512) ng/ml for LA CAB and 13.1 (12.2-13.9) ng/ml for LA RPV at delivery, and below their respective 4x protein adjusted IC 90 (PA-IC 90 ) in 100% of simulated cases (Table 1). This was above the PA-IC 90 in 100% of women at delivery for CAB LA and 79% for RPV LA. Fetal exposure based on predicted median (IQR) cord plasma level was highest during week 22 for LA CAB at 1864 (1678-1987) ng/ml and during week 28 for LA RPV at 14.6 (13.8-15.4) ng/ml. CAB and RPV were predicted to remain detectable in maternal plasma 6 months postpartum at 142 (127-159) ng/ml and 9.23 (8.24 10.1) ng/ml, respectively. Also, 17.5 and 3.5% of the women were predicted to have CAB and RPV plasma concentrations above their corresponding PA-IC 90 , respectively, at 6 months postpartum. Conclusions: The PK tails of CAB-RPV LA extend to several months postpartum, with levels falling below established minimum effective concentration in most women after gestation week 33. Potential strategies to minimise potential risks associated with CAB-RPV LA discontinuation in this population are needed. Breastfed infant exposure was not investigated in this study.

abilities while limiting adverse events recorded during pregnancy. Herein, we posit that long-acting (LA) injectable nanoformulated DTG (NDTG) can improve drug safety during pregnancy. This is expected by reducing drug exposures to placenta compared to orally administered drug. Methods: Pregnant C3H/HeJ mice (dams) were treated with daily oral DTG at a human equivalent dosage (5 mg/kg; mouse weight) from gestation day (GD) 0.5 to GD 16.5. This oral treatment was compared against pregnant mice injected with single intramuscular (IM) NDTG given at 45 mg/kg (mouse weight) at GD 0.5. Vehicle-treated group served as controls. DTG levels were measured in plasma of dams and in placenta tissues at GD 17.5 by mass spectrometry. As matrix metalloproteinases (MMPs) influence placental vascular restructuring and placenta morphogenesis, MMPs activities were determined in placentas at GD 17.5 by fluorometric assay to compare safety. Results: Both daily oral DTG administration and single IM injection of NDTG achieved equivalent therapeutic plasma drug levels (5300-6400 ng/mL) in pregnant dams. However, comparatively, two-fold lower DTG levels were quantified in placentas following NDTG injections. Specifically, an average of 1546 ng/g and 693 ng/g of DTG concentrations were measured in placenta tissues of mice treated with daily oral DTG and injectable NDTG, respectively. Higher drug levels paralleled significantly higher MMPs activities in placentas of daily oral DTG-treated mice compared to vehicle-treated (control) mice. Notably, comparative MMPs activities were recorded between control and NDTG-treated mice, suggesting the prevention of DTG-induced alterations in MMPs functions in placenta when delivered as LA injectable formulation. Conclusions: The data suggest that long-acting drug delivery can prevent DTG-linked developmental deficits during pregnancy by limiting placenta-fetal drug exposures. The figure, table, or graphic for this abstract has been removed. 1018 Population PK and CYP3A Inhibition Capacity of Ritonavir in Pregnancy: A Model-Based Meta-Analysis Jeremiah Momper 1 , Marlon Liyanage 1 , Mark Mirochnick 2 , Brookie Best 1 , Emily Barr 3 , Alice Stek 4 , Kristina Brooks 5 , Sandra Burchett 6 , Kathleen Powis 7 , Tim Cressey 8 , Edmund Capparelli 1 , Safa Algharbi 1 1 University of California San Diego, La Jolla, CA, USA, 2 Boston University, Boston, MA, USA, 3 University of Texas at Houston, Houston, TX, USA, 4 University of Southern California, Los Angeles, CA, USA, 5 University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 6 Harvard Medical School, Boston, MA, USA, 7 Massachusetts General Hospital, Boston, MA, USA, 8 Chiang Mai University, Chiang Mai, Thailand Background: Ritonavir (RTV), a strong CYP3A inhibitor, is widely used as a pharmacokinetic (PK) enhancer to increase exposure to HIV-1 protease inhibitors (PIs) and more recently the SARS CoV-2 PI nirmatrelvir. Pregnancy-related changes in RTV disposition and boosting capacity have not been systematically assessed which may inform RTV dosing in pregnancy for future emerging infectious diseases. We performed a model-based meta-analysis for the population PK (popPK) of RTV using historical data from 11 separate arms of IMPAACT P1026s, a phase IV study evaluating the PK of selected antiretroviral drugs in pregnant and postpartum women with HIV. Methods: Pregnant participants receiving RTV as a PK enhancer for either lopinavir, darunavir, or atazanavir±TDF and who were ≥20 weeks gestational age were included in the analysis. Intensive PK samples were collected pre-dose and through 24 hours post-dose in the 2nd and 3rd trimesters of pregnancy and 2-12 weeks postpartum. A popPK model was developed using non-linear mixed effects modeling (NONMEM v7.5). Results: A total of 279 participants contributing 3798 RTV plasma concentrations (565 2nd trimester, 1632 3rd trimester, and 1601 postpartum) were included. RTV concentrations were well fit with a one-compartment structural model. Pregnancy was an independent predictor of both apparent clearance (CL/F) and apparent volume of distribution (Vd/F). No other covariates significantly impacted RTV disposition. Fixed allometric scaling significantly improved the model. The following equations described the final popPK model:

Poster Abstracts

1017 A Long-Acting Dolutegravir Formulation Improves Drug Safety Profile During Pregnancy Emma G. Foster, Brady Sillman, Micah Summerlin, Christine A. Adalikwu, Baojin Yao, Yutong Liu, Benson Edagwa, Howard Gendelman, Aditya N. Bade University of Nebraska Medical Center, Omaha, NE, USA Background: Dolutegravir (DTG) is a preferred antiretroviral drug (ARV) as a part of first-line regimen for treatment of people living with human immunodeficiency virus type one (HIV-1). This includes pregnant women or those of reproductive age. Recommended DTG usage, worldwide, is linked to the drug’s potency, high genetic barrier to resistance, limited drug-drug interactions, and cost-effectiveness. Despite such benefits, there are potential risks of DTG-associated fetal developmental toxicities. Thus, novel formulation strategies with translational potential are timely to maximize DTG’s therapeutic

CL/F (L/h) = 12.0 × 1.84 (if Pregnant) × (WT/66.4) 0.75

V/F (L) = 21.1×2.27 (if Pregnant) ×(WT/66.4)

Monte Carlo simulations of 1000 virtual subjects receiving a 100 mg daily dose predicted a median AUC 0-24, ss of 3.85 and 7.09 μg*hr/mL during pregnancy

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