title: Sensitivity Analysis of a Pharmacokinetic Model of Vaginal Anti-HIV Microbicide Drug Delivery.
abstract: 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.
authors.affiliation: Mathematics, Florida State University, 208 Love Building, 1017 Academic Way, Tallahassee, Florida 32306. Electronic address: ajarrett@math.fsu.edu.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Jarrett
authors.affiliation: Department of Biomedical Engineering, Duke University, 101 Science Drive, Campus Box 90281, Durham, North Carolina 27708.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Mathematics, Florida State University, 208 Love Building, 1017 Academic Way, Tallahassee, Florida 32306.
authors.forename: M Yousuff
authors.initials: MY
authors.lastname: Hussaini
authors.affiliation: Mathematics, Florida State University, 208 Love Building, 1017 Academic Way, Tallahassee, Florida 32306.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Cogan
authors.affiliation: Department of Biomedical Engineering, Duke University, 101 Science Drive, Campus Box 90281, Durham, North Carolina 27708.
authors.forename: David F
authors.initials: DF
authors.lastname: Katz
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D008954:Models, Biological; D000068698:Tenofovir / Q000008:administration & dosage / Q000493:pharmacokinetics; D014621:Vagina / Q000187:drug effects / Q000378:metabolism* / Q000821:virology
chemical_list: D019380:Anti-HIV Agents; D000891:Anti-Infective Agents, Local; D000998:Antiviral Agents; D000068698:Tenofovir
keywords: HIV/AIDS; Monte Carlo; biophysical models; computational biology; drug design; dynamic simulation; in silico modeling; mathematical model; mucosal delivery; pharmacokinetics