Kimberly Adams (1), Thomas Straubinger (1), Sravan Kumar Patel (2,3), Peter L. Anderson (4), Dorothy Patton (5), Sharon L. Hillier (3,6), Lisa C. Rohan (2,3,6), Robert Bies (1)
(1) School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, (2) Department of Pharmaceutical Sciences, University of Pittsburgh, (3) Magee-Womens Research Institute, (4) Department of Pharmaceutical Sciences, University of Colorado, (5) Department of Obstetrics & Gynecology, University of Washington, (6) Department of Obstetrics, Gynecology, & Reproductive Sciences
Objectives: Human immunodeficiency virus (HIV) remains a significant global health challenge that disproportionately affects young women in sub-Saharan Africa [1]. Addressing this challenge requires innovative prevention strategies, such as extended-release pre-exposure prophylaxis (PrEP) formulations [2,3,4]. Vaginally administered rings and films containing MK-2048, a second-generation integrase inhibitor, are a promising strategy for HIV prevention, offering the potential for improved adherence and efficacy compared to oral dosing regimens [3,4]. Physiologically-based pharmacokinetic (PBPK) modeling is a valuable tool for evaluating the pharmacokinetic properties of these formulations [5]. This research aims to investigate the application of PBPK models in characterizing the pharmacokinetic profiles of vaginally administered extended-release PrEP formulations containing MK-2048 in non-human primates (NHP). By integrating PBPK modeling with NHP studies, we aim to provide insights into factors influencing drug absorption, distribution, and release kinetics in NHPs, therefore informing formulation optimization and dosing strategies for enhanced HIV prevention in at-risk populations.
Methods: NHP studies involved the administration of extended-release vaginal PrEP formulations containing MK-2048. A PBPK model was developed using the mrgsolve package in R to simulate the pharmacokinetic profiles of MK-2048 in NHPs, incorporating physiological parameters specific to NHP species and the vaginal route of administration [6]. The model integrated drug-specific characteristics of MK-2048, such as protein binding, ionization, and release kinetics, alongside NHP-specific physiological parameters.
Results: The developed PBPK model successfully captured the pharmacokinetic profiles of MK-2048 in vaginally administered extended-release PrEP formulations in NHP models, demonstrating good agreement with observed data. Key adjustments to the model to capture the observed data included 1.) the release from the formulation, 2.) drug species capable of moving throughout the vaginal space, 3.) the first order rate constants between the vaginal fluid, tissue, and blood supply and 4.) the clearance terms. Model validation using different NHP study data confirmed the robustness and reliability of the PBPK model in predicting MK-2048 pharmacokinetics in the vaginal space and plasma. The model provides insights into the key factors influencing drug absorption, distribution, and release kinetics in NHPs, including the formulation type, thus facilitating formulation optimization and dosing strategies for enhanced HIV prevention.
Conclusions: This research highlights the utility of PBPK modeling to help understand the pharmacokinetic behavior of vaginally administered extended-release PrEP formulations containing MK-2048 in NHPs. Integrating mechanistic insights from PBPK models with experimental data from NHP studies facilitates the rational design and optimization of PrEP formulations for enhanced HIV prevention efficacy in humans. Leveraging NHP models to scale these findings to human populations presents a robust approach for translating preclinical data into clinically relevant strategies. This integrated methodology emphasizes the relationship among formulation characteristics, vaginal physiology, and dosing regimens in extended-release PrEP strategies with MK-2048 and other vaginally administered formulations. In the future, continued development and refinement of this PBPK model are essential for translating these insights into improvements in HIV prevention strategies.
References:
[1] UNAIDS. Global HIV & AIDS statistics – Fact sheet. 2022; https://www.unaids.org/en/resources/fact-sheet
[2] Kay K, Shah DK, Rohan L, Bies R. Physiologically-based pharmacokinetic model of vaginally administered dapivirine ring and film formulations. Br J Clin Pharmacol. 2018;84(9):1950-1969
[3]Hoesley CJ, Chen BA, Anderson PL, et al. Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings. Clin Infect Dis. 2019;68(7):1136-1143.
[4] Liu AY, Zhang J, Anderson PL, et al. Phase 1 Pharmacokinetic Trial of 2 Intravaginal Rings Containing Different Dose Strengths of Vicriviroc (MK-4176) and MK-2048. Clin Infect Dis. 2019;68(7):1129-1135.
[5] Jones H, Rowland-Yeo K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT Pharmacometrics Syst Pharmacol. 2013;2:e63.
[6] https://mrgsolve.org/
Reference: PAGE 32 (2024) Abstr 11075 [www.page-meeting.org/?abstract=11075]
Poster: Drug/Disease Modelling - Absorption & PBPK