title: Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women.
abstract: Vaginal microbicides for the prevention of HIV transmission may be an important option for protecting women from infection. Incorporation of dapivirine, a lead candidate nonnucleoside reverse transcriptase inhibitor, into intravaginal rings (IVRs) for sustained mucosal delivery may increase microbicide product adherence and efficacy compared with conventional vaginal formulations. Twenty-four healthy HIV-negative women 18-35 years of age were randomly assigned (1:1:1) to dapivirine matrix IVR, dapivirine reservoir IVR, or placebo IVR. Dapivirine concentrations were measured in plasma and vaginal fluid samples collected at sequential time points over the 33-day study period (28 days of IVR use, 5 days of follow-up). Safety was assessed by pelvic/colposcopic examinations, clinical laboratory tests, and adverse events. Both IVR types were safe and well tolerated with similar adverse events observed in the placebo and dapivirine groups. Dapivirine from both IVR types was successfully distributed throughout the lower genital tract at concentrations over 4 logs greater than the EC50 against wild-type HIV-1 (LAI) in MT4 cells. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) values were significantly higher with the matrix than reservoir IVR. Mean plasma concentrations of dapivirine were <2 ng/mL. These findings suggest that IVR delivery of microbicides is a viable option meriting further study.
authors.affiliation: International Partnership for Microbicides, Silver Spring, MD, USA.
authors.forename: Annalene
authors.initials: A
authors.lastname: Nel
authors.forename: Shanique
authors.initials: S
authors.lastname: Smythe
authors.forename: Katherine
authors.initials: K
authors.lastname: Young
authors.forename: Karl
authors.initials: K
authors.lastname: Malcolm
authors.forename: Clare
authors.initials: C
authors.lastname: McCoy
authors.forename: Zeda
authors.initials: Z
authors.lastname: Rosenberg
authors.forename: Joseph
authors.initials: J
authors.lastname: Romano
mesh_terms: D000282:Administration, Intravaginal; D000293:Adolescent; D000328:Adult; D003127:Colposcopy; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D014621:Vagina / Q000378:metabolism
chemical_list: D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C481671:Dapivirine