Sensitivity Analysis of a Pharmacokinetic Model of Vaginal Anti-HIV Microbicide Drug Delivery.

Journal Article

Uncertainties in parameter values in microbicide pharmacokinetics (PK) models confound the models' use in understanding the determinants of drug delivery and in designing and interpreting dosing and sampling in PK studies. A global sensitivity analysis (Sobol' indices) was performed for a compartmental model of the pharmacokinetics of gel delivery of tenofovir to the vaginal mucosa. The model's parameter space was explored to quantify model output sensitivities to parameters characterizing properties for the gel-drug product (volume, drug transport, initial loading) and host environment (thicknesses of the mucosal epithelium and stroma and the role of ambient vaginal fluid in diluting gel). Greatest sensitivities overall were to the initial drug concentration in gel, gel-epithelium partition coefficient for drug, and rate constant for gel dilution by vaginal fluid. Sensitivities for 3 PK measures of drug concentration values were somewhat different than those for the kinetic PK measure. Sensitivities in the stromal compartment (where tenofovir acts against host cells) and a simulated biopsy also depended on thicknesses of epithelium and stroma. This methodology and results here contribute an approach to help interpret uncertainties in measures of vaginal microbicide gel properties and their host environment. In turn, this will inform rational gel design and optimization.

Full Text

Duke Authors

Cited Authors

  • Jarrett, AM; Gao, Y; Hussaini, MY; Cogan, NG; Katz, DF

Published Date

  • May 2016

Published In

Volume / Issue

  • 105 / 5

Start / End Page

  • 1772 - 1778

PubMed ID

  • 27012224

Electronic International Standard Serial Number (EISSN)

  • 1520-6017

International Standard Serial Number (ISSN)

  • 0022-3549

Digital Object Identifier (DOI)

  • 10.1016/j.xphs.2016.02.015

Language

  • eng