title: Compartmental transport model of microbicide delivery by an intravaginal ring.
abstract: Topical antimicrobials, or microbicides, are being developed to prevent HIV transmission through local, mucosal delivery of antiviral compounds. While hydrogel vehicles deliver the majority of current microbicide products, intravaginal rings (IVRs) are an alternative microbicide modality in preclinical development. IVRs provide a long-term dosing alternative to hydrogel use, and might provide improved user adherence. IVR efficacy requires sustained delivery of antiviral compounds to the entire vaginal compartment. A two-dimensional, compartmental vaginal drug transport model was created to evaluate the delivery of drugs from an intravaginal ring. The model utilized MRI-derived ring geometry and location, experimentally defined ring fluxes and vaginal fluid velocities, and biophysically relevant transport theory. Model outputs indicated the presence of potentially inhibitory concentrations of antiviral compounds along the entire vaginal canal within 24 h following IVR insertion. Distributions of inhibitory concentrations of antiviral compounds were substantially influenced by vaginal fluid flow and production, while showing little change due to changes in diffusion coefficients or ring fluxes. Additionally, model results were predictive of in vivo concentrations obtained in clinical trials. Overall, this analysis initiates a mechanistic computational framework, heretofore missing, to understand and evaluate the potential of IVRs for effective delivery of antiviral compounds.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. anthony.geonnotti@duke.edu
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Geonnotti
authors.forename: David F
authors.initials: DF
authors.lastname: Katz
mesh_terms: D000042:Absorption; D000282:Administration, Intravaginal; D000465:Algorithms; D019380:Anti-HIV Agents / Q000008:administration & dosage; D000890:Anti-Infective Agents / Q000008:administration & dosage*; D001826:Body Fluids / Q000378:metabolism; D003198:Computer Simulation; D004058:Diffusion; D005260:Female; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D007700:Kinetics; D008279:Magnetic Resonance Imaging; D009092:Mucous Membrane / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism; D012984:Software; D014621:Vagina / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C481671:Dapivirine