Computational Modeling of Antiviral Drug Diffusion from Poly(lactic-co-glycolic-acid) Fibers and Multicompartment Pharmacokinetics for Application to the Female Reproductive Tract

Abstract

The need for more versatile technologies to deliver antiviral agents to the female reproductive tract (FRT) has spurred the development of on-demand and sustained-release platforms. Electrospun fibers (EFs), in particular, have recently been applied to FRT delivery, resulting in an alternative dosage form with the potential to provide protection and therapeutic effect against a variety of infection types. However, a multitude of fabrication parameters, as well as the resulting complexities of solvent-drug, drug-polymer, and solvent-polymer interactions, are known to significantly impact the loading and release of incorporated agents. Numerous processing parameters, in addition to their combined interactions, can hinder the iterative development of fiber formulations to achieve optimal release for particular durations, doses, and polymer-drug types. The experimental effort to design and develop EFs could benefit from mathematical analysis and computational simulation that predictively evaluate combinations of parameters to meet product design needs. Here, existing modeling efforts are leveraged to develop a simulation platform that correlates and predicts the delivery of relevant small molecule antivirals from EFs that have been recently applied to target sexually transmitted infections (STIs). A pair of mathematical models is coupled to simulate the release of two structurally similar small molecule antiretroviral reverse transcriptase inhibitors, Tenofovir (TFV) and Tenofovir disoproxil fumarate (TDF), from poly(lactic- co-glycolic acid) (PLGA) EFs, and to evaluate how changes in the system parameters affect the distribution of encapsulated agent in a three-compartment model of the vaginal epithelium. The results indicate that factors such as fiber diameter, mesh thickness, antiviral diffusivity, and fiber geometry can be simulated to create an accurate model that distinguishes the different release patterns of TFV and TDF from EFs, and that enables detailed evaluation of the associated pharmacokinetics. This simulation platform offers a basis with which to further study EF parameters and their effect on antiviral release and pharmacokinetics in the FRT.

Nanoparticle-mediated drug delivery to treat infections in the female reproductive tract: evaluation of experimental systems and the potential for mathematical modeling

“…Very recently, a model of PLGA polymer degradation 92 was adapted to simulate degradation and release of TFV and tenofovir disoproxil fumarate (TDF) from an electrospun PLGA fiber. 93 TFV and TDF are structurally similar molecules, yet with very different release and distribution profiles. The model output was then incorporated into a two-dimensional (2D)…”

“…This framework consisting of two coupled models offers the capability to study variation in fiber degradation and drug release, and how these parameters in turn may affect drug distribution in tissue. 93 Studies conducted by Katz et al have highlighted the fundamental mass transport principles and applications related to the diffusion and convection of drugs and small molecules through the vaginal environment. 1,82,89,91 This work has focused on the use of models to investigate the PK and PD of tenofovir -and its associated derivative, TDF -when topically delivered to the vagina using either a gel 1,91 or intravaginal ring, 1,89 with differing dosage regimens.…”

“…Mathematical modeling could be applied to tailor such NPs to have mucoadhesive properties, to "stick" to the mucus layer, slowly releasing drug at this location, or to utilize muco-inert features to penetrate the epithelium and release drug within the stroma. Further, the coupling of various models -such as drug release from electrospun fibers with drug diffusion within the FRT 93 -holds the promise for an integrated understanding of therapeutic efficacy. Ultimately, the development of modeling frameworks that include user, therapeutic, and physiological characteristics may offer practical tools to complement current clinical approaches by informing therapeutic design that is personalized to individual patient needs.…”

PLGA-modified nanoparticles for the treatment of hypo-vascularized HPV-related cervical cancers.

“…2). 93 The results indicate that factors such as antiviral diffusivity, mesh thickness, fiber diameter, and geometry can be simulated to create an accurate model that distinguishes the very different release profiles of tenofovir and TDF observed in vaginal tissue.…”

“…Mathematical modeling could be applied to tailor such NPs to have mucoadhesive properties, to "stick" to the mucus layer, slowly releasing drug at this location, or to utilize muco-inert features to penetrate the epithelium and release drug within the stroma. Further, the coupling of various models, such as drug release from electrospun fibers with drug diffusion within the FRT,93 holds the promise for an integrated understanding of therapeutic efficacy. Ultimately, the development of modeling frameworks that include user, therapeutic, and physiological characteristics may offer practical tools to complement current clinical approaches by informing therapeutic design that is personalized to individual patient needs.D.…”