title: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: A Double-Blind Randomized Trial.
abstract: BACKGROUND
  Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery.
  
  
  METHODS
  MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics.
  
  
  RESULTS
  There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels.
  
  
  CONCLUSIONS
  In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed.
authors.affiliation: *Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA; †Magee-Womens Research Institute, Pittsburgh, PA; ‡Department of Medicine and Infectious Disease, Fenway Institute, Boston, MA; §Department of Pathology and Medicine, Johns Hopkins University, Baltimore, MD; ‖Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; ¶Women's Global Health Imperative (WGHI) RTI International, San Francisco, CA; #Center for AIDS Prevention Studies, University of California San Francisco, Department of Medicine, San Francisco, CA; **Statistical Center for HIV/AIDS Research & Prevention/Fred Hutchinson Cancer Research Center, Seattle, WA; ††NIAID/DAIDS, Bethesda, MD; ‡‡International Partnership for Microbicides, Silver Spring, MD; §§FHI 360, Durham, NC; and ‖‖Alpha StatConsult, Damascus, MD.
authors.forename: Beatrice A
authors.initials: BA
authors.lastname: Chen
authors.forename: Lori
authors.initials: L
authors.lastname: Panther
authors.forename: Mark A
authors.initials: MA
authors.lastname: Marzinke
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Hoesley
authors.forename: Ariane
authors.initials: A
authors.lastname: van der Straten
authors.forename: Marla J
authors.initials: MJ
authors.lastname: Husnik
authors.forename: Lydia
authors.initials: L
authors.lastname: Soto-Torres
authors.forename: Annalene
authors.initials: A
authors.lastname: Nel
authors.forename: Sherri
authors.initials: S
authors.lastname: Johnson
authors.forename: Nicola
authors.initials: N
authors.lastname: Richardson-Harman
authors.forename: Lorna K
authors.initials: LK
authors.lastname: Rabe
authors.forename: Charlene S
authors.initials: CS
authors.lastname: Dezzutti
mesh_terms: D000282:Administration, Intravaginal; D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003510:Cyclohexanes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006207:Half-Life; D006801:Humans; D000077592:Maraviroc; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D003510:Cyclohexanes; D004338:Drug Combinations; D011743:Pyrimidines; D014230:Triazoles; D000077592:Maraviroc; C481671:Dapivirine