P15.17
Background: Understanding microbicide functionality, product design and evaluation derive from synergy of experimental (in vitro, in vivo) and computational (modeling) analyses. Modeling can deconstruct and elucidate many elements of cause and effect in this complex, multivariate process. Its potential has not been fully realized in the science and development of anti-HIV strategies, e.g. in pharmacokinetic analysis. Mechanistic modeling of microbicide PK processes - for different vehicles (e.g. gels, rings) and different types of drugs - can provide a framework to:
(1) identify salient properties of vehicle, drug, host environment and dose regimen that govern PK;
(2) input those properties to make quantitative comparisons and predictions that help design and interpret in vivo studies in humans and animals, and in vitro studies of drug release/transport and HIV neutralization.
Methods: Principles of mass transport theory were applied to vaginal delivery of microbicide drugs by clinical and prototype gels and rings. Compartments in the models were vehicle, lumenal fluids, epithelium, stroma and blood stream. Diffusion and convection were primary mechanisms of drug transport. Systems of coupled partial differential equations were derived/solved, outputting drug concentrations vs. time/location in each compartment.
Results: Results include tradeoffs in gel volume (2-4 mL) and loading (0.5-1.5%) for Tenofovir, IQP0528 and other drugs in achieving mucosal concentrations that reach prophylactic (e.g. EC50) levels, showing how frequency of dosing can sustain these levels. IVR geometry and release flux history are related to such target concentrations, including effects of transient ring removal. Scaling rules for human vs. animal dosing are given.
Conclusions: Mechanistic modeling fills gaps in microbicide drug delivery science, helping define and organize effects of the many factors involved. This knowledge translates to methodology for use in rational product design and performance evaluation, in vitro and in vivo.
