Concentrations of Dapivirine in the Rhesus Macaque and Rabbit following Once Daily Intravaginal Administration of a Gel Formulation of [ 14 C]Dapivirine for 7 Days
- 1 March 2008
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 52 (3), 909-914
- https://doi.org/10.1128/aac.00330-07
Abstract
Dapivirine is a nonnucleoside reverse transcriptase inhibitor being developed as a topical microbicide for the prevention of human immunodeficiency virus infection. The distribution of radioactivity and drug in plasma and in vaginal, cervical, and draining lymph node tissues was investigated after daily application of a vaginal gel formulation of [ 14 C]dapivirine to rhesus macaques. This was preceded by a preliminary study with rabbits. Following the intravaginal administration of [ 14 C]dapivirine (∼0.1 mg/ml [15 μCi/ml]) to rabbits (0.5 ml/day) and macaques (1 ml/day) for 7 days, the dapivirine levels associated with vaginal and cervical tissue samples 1 h after the final dose were high (quantities of μg/g of tissue) and remained detectable at 24 h (mean, ≥2.5 ng/g in rabbits) and 48 h (mean, >80 ng/g in macaques). Radioactivity levels were low in the plasma and very low or unquantifiable in the draining lymph nodes of the macaques. Microautoradiography identified drug-related material (DRM) on the surfaces of the vaginal and cervical tissues of the rabbits and macaques. Although DRM was primarily associated with the outermost layer of shedding cells in rabbits, two animals showed some evidence of small quantities in the mucosal epithelium of the cervix. In macaques, DRM was seen within the keratinized layer of the vaginal epithelium and and was found to extend into the superficial cellular layers, and in at least one animal it appeared to be present in the deepest (germinal) layer of the epithelium and in submucosal tissues. The persistence of biologically significant concentrations of dapivirine in vaginal and cervical tissues for >24 h supports the development of dapivirine as a microbicide for once daily application.Keywords
This publication has 9 references indexed in Scilit:
- Dose-Ranging Phase 1 Study of TMC120, a Promising Vaginal Microbicide, in HIV-Negative and HIV-Positive Female VolunteersJAIDS Journal of Acquired Immune Deficiency Syndromes, 2007
- Dawn of non-nucleoside inhibitor-based anti-HIV microbicidesJournal of Antimicrobial Chemotherapy, 2006
- The Nonnucleoside Reverse Transcriptase Inhibitor UC-781 Inhibits Human Immunodeficiency Virus Type 1 Infection of Human Cervical Tissue and Dissemination by Migratory CellsJournal of Virology, 2005
- HIV and sexually transmitted diseases: lethal synergy.2004
- Recent advances in the development of next generation non-nucleoside reverse transcriptase inhibitors.Current Topics in Medicinal Chemistry, 2004
- Roles of Conformational and Positional Adaptability in Structure-Based Design of TMC125-R165335 (Etravirine) and Related Non-nucleoside Reverse Transcriptase Inhibitors That Are Highly Potent and Effective against Wild-Type and Drug-Resistant HIV-1 VariantsJournal of Medicinal Chemistry, 2004
- In Vitro Evaluation of Nonnucleoside Reverse Transcriptase Inhibitors UC-781 and TMC120-R147681 as Human Immunodeficiency Virus MicrobicidesAntimicrobial Agents and Chemotherapy, 2004
- Disruption of the upper female reproductive tract epithelium by nonoxynol-9Contraception, 2003
- Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulationAIDS, 2003