Deducing Mucosal Pharmacokinetics and Pharmacodynamics of the Anti-HIV Molecule Tenofovir from Measurements in Blood

Abstract

Microbicide pharmacokinetic (PK) studies typically sample drug in luminal fluid, mucosal tissue, and blood. Blood measurements can be conducted most frequently, serially within subjects. Antiretroviral drugs, however, act against HIV in mucosal tissue/cells. We computationally modeled the extent measurements in blood can predict concentrations in tissue, focusing on the antiretroviral drug tenofovir delivered by a vaginal gel. Deterministic PK models input host and product factors and output spatiotemporal drug concentrations in luminal fluid, epithelium, stroma/host cells, and blood. Pharmacodynamic (PD) analysis referenced stroma/host cell concentrations to prophylactic values; summary metrics were time from product insertion to protection (tlag) and degree of protection (PPmax). Results incorporated host factors characteristic of population variability. Neural nets (NN) linked simulated blood PK metrics (Cmax, tmax, AUC, C24) to mucosal PK/PD metrics. The NNs delivered high-performance mapping of these multiparametric relationships. Given multi-log variability typical of biopsy data for tenofovir and other topical microbicides, results suggest downstream but higher fidelity measurements in blood could help improve determination of PK and create inferences about PD. Analysis here is for a tenofovir gel, but this approach offers promise for application to other microbicide modalities and to topical drug delivery to vaginal mucosa more generally.

Modelling And Simulation of Topical Drug Diffusion in The Dermal Layer of Human Body

“…A number of researchers reported their research results on topical drug diffusion problem in the dermal layer in human body [1][2][3][4][5][6][7][8][9][10]. Some of them use the molecular nanotechnology point of view [11][12][13][14]. In line with them, Sharma and Saxena [15] worked on finite element modelling in transdermal delivery system of drug especially when the case is at the steady state condition.…”

Modeling HIV Pre-Exposure Prophylaxis

“…Recently, Govil and Katz published a proof of concept study of a modelling approach utilizing feedforward neural networks to link plasma pharmacokinetic models of TFV to vaginal tissue PK and PD endpoints. (Govil and Katz, 2019) Emtricitabine Emtricitabine (FTC) is a nucleoside reverse transcriptase inhibitor effective against HIV-1. In the context of PrEP, FTC is administered as a combination oral therapy with the NRTI tenofovir disoproxil fumarate.…”