Physiologically‐based pharmacokinetic model of vaginally administered dapivirine ring and film formulations

Abstract

AimsA physiologically‐based pharmacokinetic (PBPK) model of the vaginal space was developed with the aim of predicting concentrations in the vaginal and cervical space. These predictions can be used to optimize the probability of success of vaginally administered dapivirine (DPV) for HIV prevention. We focus on vaginal delivery using either a ring or film.MethodsA PBPK model describing the physiological structure of the vaginal tissue and fluid was defined mathematically and implemented in MATLAB. Literature reviews provided estimates for relevant physiological and physiochemical parameters. Drug concentration–time profiles were simulated in luminal fluids, vaginal tissue and plasma after administration of ring or film. Patient data were extracted from published clinical trials and used to test model predictions.ResultsThe DPV ring simulations tested the two dosing regimens and predicted PK profiles and area under the curve of luminal fluids (29 079 and 33 067 mg h l–1 in groups A and B, respectively) and plasma (0.177 and 0.211 mg h l–1) closely matched those reported (within one standard deviation). While the DPV film study reported drug concentration at only one time point per patient, our simulated profiles pass through reported concentration range.ConclusionsHIV is a major public health issue and vaginal microbicides have the potential to provide a crucial, female‐controlled option for protection. The PBPK model successfully simulated realistic representations of drug PK. It provides a reliable, inexpensive and accessible platform where potential effectiveness of new compounds and the robustness of treatment modalities for pre‐exposure prophylaxis can be evaluated.

Review of Complex Generic Drugs Delivered Through the Female Reproductive Tract: The Current Competitive Landscape and Emerging Role of Physiologically Based Pharmacokinetic Modeling to Support Development and Regulatory Decisions

“…However, to the best of the authors' knowledge, there are no generalized PBPK modeling and simulation platforms that characterize both intravaginal and intrauterine drug delivery. To date, the only PBPK models of drug delivery to the female reproductive tract available in the public domain appear to be a model of intravaginal delivery of dapivirine published by Kay et al 27 and a model of intrauterine delivery of levonorgestrel submitted in NDA 203159 for the SKYLA (levonorgestrel) intrauterine device 13.5 mg. 28 It is important to note that the PBPK model by Kay et al is limited to the vaginal and lower cervical space and contains model parameter values specific to dapivirine. 27 In general, there are limited data available on the anatomic and physiological determinants of drug delivery via the female reproductive tract.…”

“…To date, the only PBPK models of drug delivery to the female reproductive tract available in the public domain appear to be a model of intravaginal delivery of dapivirine published by Kay et al 27 and a model of intrauterine delivery of levonorgestrel submitted in NDA 203159 for the SKYLA (levonorgestrel) intrauterine device 13.5 mg. 28 It is important to note that the PBPK model by Kay et al is limited to the vaginal and lower cervical space and contains model parameter values specific to dapivirine. 27 In general, there are limited data available on the anatomic and physiological determinants of drug delivery via the female reproductive tract. Although measurements of tissue volumes, compositions, and blood flow rates are described in the literature, many of the data appear to characterize the physiological changes occurring during pregnancy, rather than normal baseline values in healthy, nonpregnant, adult females.…”

In vitro release testing methods for drug-releasing vaginal rings

“…Finally, a physiologically-based pharmacokinetic model -the structural compartments of which comprise the vaginal epithelium, vaginal stroma, lungs, liver and the rest of body -has recently been reported for quantitative prediction of cervicovaginal tissue and plasma concentrations for the 25 mg matrix-type dapivirine vaginal ring (Ring-004, Table 1) [165]. (Fig.…”

Antiretroviral agents in pre-exposure prophylaxis: emerging and advanced trends in HIV prevention

“…PBPK was developed to estimate the concentration of DPV in cervical and vaginal space. This model helps to simulate the pharmacokinetics of DPV films and vaginal rings in this case . A study was done to determine the acceptability of a vaginal ring and adherence to it.…”