title: Pharmacokinetic modeling of a gel-delivered dapivirine microbicide in humans.
abstract: Although a number of drugs have been developed for the treatment and prevention of human immunodeficiency virus (HIV) infection, it has proven difficult to optimize the drug and dosage parameters. The vaginal tissue, comprised of epithelial, stromal and blood compartments presents a complex system which challenges evaluation of drug kinetics solely through empirical effort. To provide insight into the underlying processes, mathematical modeling and computational simulation have been applied to the study of retroviral microbicide pharmacokinetics. Building upon previous pioneering work that modeled the delivery of Tenofovir (TFV) via topical delivery to the vaginal environment, here we computationally evaluate the performance of the retroviral inhibitor dapivirine released from a microbicide gel. We adapt the TFV model to simulate the multicompartmental diffusion and uptake of dapivirine into the blood plasma and vaginal compartments. The results show that dapivirine is expected to accumulate at the interface between the gel and epithelium compartments due to its hydrophobic characteristics. Hydrophobicity also results in decreased diffusivity, which may impact distribution by up to 2 orders of magnitude compared to TFV. Maximum concentrations of dapivirine in the epithelium, stroma, and blood were 9.9e7, 2.45e6, and 119pg/mL, respectively. This suggests that greater initial doses or longer time frames are required to obtain higher drug concentrations in the epithelium. These observations may have important ramifications if a specific time frame is required for efficacy, or if a minimum/maximum concentration is needed in the mucus, epithelium, or stroma based on combined efficacy and safety data.
authors: Department of Bioengineering, University of Louisville, Louisville, KY, USA.
authors: Michael E
authors: ME
authors: Halwes
authors: Department of Bioengineering, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA; Center for Predictive Medicine, University of Louisville, Louisville, KY, USA.
authors: Jill M
authors: JM
authors: Steinbach-Rankins
authors: Department of Bioengineering, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. Electronic address: hbfrie01@louisville.edu.
authors: Hermann B
authors: HB
authors: Frieboes
mesh_terms: D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005782:Gels; D006801:Humans; D008954:Models, Biological; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014621:Vagina / Q000378:metabolism; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000890:Anti-Infective Agents; D004337:Drug Carriers; D005782:Gels; D011743:Pyrimidines; D014622:Vaginal Creams, Foams, and Jellies; C481671:Dapivirine
keywords: Computational modeling; Dapivirine; Human immunodeficiency virus; Microbicide gel; Pharmacokinetics; Retroviral drug