THI THANH TRAN 1, KHANH LINH DUONG 2, THI THAM BUI 3, Do Chris 6, Soyoung Lee 1,4,5, Hwi-yeol Yun 1,4,5, Jung-woo Chae 1,4,5,6, Jeremiah D. Momper 6
1 College of Pharmacy, Chungnam National University (Yuseong-gu, Daejeon, Republic of Korea), 2 Faculty of Pharmacy, Hanoi University of Pharmacy (Hanoi, Vietnam), 3 Faculty of Pharmacy, Haiphong University of Medicine and Pharmacy (Hai Phong, Vietnam), 4 Bio-AI Convergence Research Center, Chungnam National University (Yuseong-gu, Daejeon, Republic of Korea), 5 Senior Health Convergence Research Center, Chungnam National University (Yuseong-gu, Daejeon, Republic of Korea), 6 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California - San Diego (Sandiego, California (CA), USA)
Objectives: Rilpivirine (RPV) systemic exposure decreases by approximately 30-50% during the second and third trimesters of pregnancy, raising concerns about subtherapeutic drug concentrations and reduced antiviral efficacy. Although RPV is also administered as a long-acting injectable formulation in combination with cabotegravir (Cabenuva), quantitative, trimester-specific guidance for oral dose adjustment remains limited. This study aimed to develop and clinically validate a physiologically based pharmacokinetic (PBPK) model and establish a simulation-informed framework to support individualized oral RPV dosing in pregnant women living with HIV throughout gestation.
Methods: Physicochemical properties and pharmacokinetic data were collected from the literature, and plasma concentration-time profiles were digitized using WebPlotDigitizer. An oral RPV PBPK model was first developed and validated in non-pregnant adults using PK-Sim. Pregnancy specific physiological changes, including alterations in CYP3A4 mediated metabolism and plasma protein binding, were subsequently integrated using MoBi. The pregnancy PBPK model was validated against clinical pharmacokinetic data from the PKRxiv repository and five published clinical studies. Model-based simulations were conducted in a virtual population of 1,000 pregnant women to evaluate gestational age-specific dosing strategies against predefined efficacy and safety targets.
Results: The model accurately predicted RPV pharmacokinetics in both non-pregnant adults and pregnant women. Predicted AUClast and Cmax values were within two-fold of observed clinical data. To maintain target trough concentration of 50 ng/mL, consistent with French national HIV guidelines, dosing regimens of 37.5 mg once daily in the second and 50 mg once daily in the third trimester were identified. All proposed regimens maintained predicted Cmax values below the 500 ng/mL safety threshold associated with clinically relevant QTc prolongation, thus balancing antiviral efficacy with cardiac safety during pregnancy.
Conclusions: This study provides a clinically validated, simulation-informed PBPK framework for trimester-specific dose optimization of oral rilpivirine in pregnant women living with HIV. The proposed model-based dosing strategy offers a quantitative approach to support individualized treatment, inform clinical decision making, and guide future trial design in this vulnerable population. Additional investigation is warranted to determine whether similar trimester-specific considerations apply to long-acting injectable rilpivirine formulations.
T. T Tran, K. L Duong, T. T Bui contributed equally as co-first authors; corresponding authors: H.-y. Yun, S. Lee, J.-w. Chae, and M. D Momper.
References:
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Reference: PAGE 34 (2026) Abstr 12277 [www.page-meeting.org/?abstract=12277]
Poster: Clinical Applications