title: First-in-Human Trial of MIV-150 and Zinc Acetate Coformulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence, and Pharmacodynamics.
abstract: OBJECTIVE
  To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored.
  
  
  METHODS
  A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days.
  
  
  METHODS
  Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose-response inhibition analysis.
  
  
  RESULTS
  Participants (n = 20) ranged from 19-44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti-herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity.
  
  
  CONCLUSIONS
  PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti-human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted infection prevention.
authors.affiliation: *The Population Council, New York, NY; and †University of Alabama at Birmingham; Birmingham, AL.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Friedland
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Hoesley
authors.forename: Marlena
authors.initials: M
authors.lastname: Plagianos
authors.forename: Elena
authors.initials: E
authors.lastname: Hoskin
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhang
authors.forename: Natalia
authors.initials: N
authors.lastname: Teleshova
authors.forename: Mohcine
authors.initials: M
authors.lastname: Alami
authors.forename: Lea
authors.initials: L
authors.lastname: Novak
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Kleinbeck
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Katzen
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Zydowsky
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández-Romero
authors.forename: George W
authors.initials: GW
authors.lastname: Creasy
mesh_terms: D000282:Administration, Intravaginal; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002351:Carrageenan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D004311:Double-Blind Method; D005260:Female; D005782:Gels / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D055118:Medication Adherence; D010342:Patient Acceptance of Health Care; D010919:Placebos / Q000008:administration & dosage; D065129:Pre-Exposure Prophylaxis / Q000379:methods*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015229:Sexually Transmitted Diseases, Viral / Q000517:prevention & control*; D053719:Tandem Mass Spectrometry; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult; D019345:Zinc Acetate / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D005782:Gels; C510296:MIV 150; D010919:Placebos; D011725:Pyridines; D014508:Urea; D002351:Carrageenan; D019345:Zinc Acetate