Concentrations of dapivirine in the rhesus macaque and rabbit following once daily intravaginal administration of a gel formulation of [14C]dapivirine for 7 days.
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 [14C]dapivirine to rhesus macaques. This was preceded by a preliminary study with rabbits. Following the intravaginal administration of [14C]dapivirine ( approximately 0.1 mg/ml [15 microCi/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 microg/g of tissue) and remained detectable at 24 h (mean, >or=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.
Nuttall
Jeremy P
JP
International Partnership for Microbicides, 8401 Colesville Road, Suite 200, Silver Spring, MD 20910, USA. jnuttall@ipm-microbicides.org
Thake
Daryl C
DC
Lewis
Mark G
MG
Ferkany
John W
JW
Romano
Joseph W
JW
Mitchnick
Mark A
MA
D000282:Administration, Intravaginal; D000818:Animals; D002250:Carbon Radioisotopes / Q000378:metabolism*; D002584:Cervix Uteri / Q000378:metabolism; D005260:Female; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011817:Rabbits; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D013997:Time Factors; D014621:Vagina / Q000378:metabolism; D014622:Vaginal Creams, Foams, and Jellies
D002250:Carbon Radioisotopes; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D014622:Vaginal Creams, Foams, and Jellies; D054303:HIV Reverse Transcriptase; C481671:Dapivirine