title: Pharmacokinetic assessment of dapivirine vaginal microbicide gel in healthy, HIV-negative women.
abstract: To assess the pharmacokinetics of dapivirine in plasma and dapivirine concentrations in cervicovaginal fluids (CVF) and cervicovaginal tissues following vaginal administration of dapivirine microbicide gel in healthy, HIV-negative women for 10 days. A randomized, double-blind, phase I study was conducted at a single research center in South Africa. A total of 18 women used dapivirine gel (0.001%, 0.005%, or 0.02%) once daily on Days 1 and 10 and twice daily on Days 2-9. Pharmacokinetics of dapivirine were assessed in plasma on Days 1 and 10. Dapivirine concentrations were measured in CVF on Days 1 and 10 and in cervicovaginal tissues on Day 10. Safety was evaluated through laboratory tests (hematology, clinical chemistry, and urinalysis), physical examinations, and assessment of adverse events. Plasma concentrations of dapivirine increased over time with gel dose and were greater on Day 10 (C(max) 31 to 471 pg/ml) than Day 1 (C(max) 23 to 80 pg/ml). T(max) was 10-12 h on Day 1, and 9 h on Day 10. Concentrations in CVF generally increased with dose but were highly variable among participants. Mean peak values ranged from 4.6-8.3 × 10(6) pg/ml on Day 1 and from 2.3-20.7 × 10(6) pg/ml on Day 10 across dose groups. Dapivirine was detectable in all tissue biopsies on Day 10 at concentrations of 1.0-356 × 10(3) pg/mg.
  
  
  CONCLUSIONS
  Dapivirine was widely distributed throughout the lower genital tract with low systemic absorption when administered in a vaginal gel formulation for 10 consecutive days. The gel was safe and well tolerated.
authors.affiliation: International Partnership for Microbicides, Silver Spring, Maryland 20910, USA.
authors.forename: Annalene M
authors.initials: AM
authors.lastname: Nel
authors.forename: Paul
authors.initials: P
authors.lastname: Coplan
authors.forename: Shanique C
authors.initials: SC
authors.lastname: Smythe
authors.forename: Karen
authors.initials: K
authors.lastname: McCord
authors.forename: Mark
authors.initials: M
authors.lastname: Mitchnick
authors.forename: Paulina E
authors.initials: PE
authors.lastname: Kaptur
authors.forename: Joseph
authors.initials: J
authors.lastname: Romano
mesh_terms: D000282:Administration, Intravaginal; D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D012634:Bodily Secretions / Q000737:chemistry; D002584:Cervix Uteri / Q000737:chemistry; D004311:Double-Blind Method; D005260:Female; D005782:Gels / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D010949:Plasma / Q000737:chemistry; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D013019:South Africa; D014621:Vagina / Q000737:chemistry
chemical_list: D000890:Anti-Infective Agents; D005782:Gels; D011743:Pyrimidines; C481671:Dapivirine