A first-in-human trial of MIV-150 and zinc acetate co-formulated in a carrageenan gel: Safety, pharmacokinetics, acceptability, adherence and pharmacodynamics
Objective: To evaluate the safety and pharmacokinetics (PK) of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics (PD) were also explored. Design: 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 14d. Methods: Assessments included physical exams, 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 LCMS-MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability and adherence were analyzed descriptively. PK parameters were calculated using non-compartmental 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. 7/7 CVLs collected 4h post-dose demonstrated antiviral (HIV, HPV) activity. High baseline CVL anti-HSV-2 activity precluded assessment of post-dose activity. Conclusion: PC-1005 used vaginally for 14d was well-tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Post-dose CVLs had anti-HIV and anti-HPV activity. These data warrant further development of PC-1005 for HIV and STI prevention.
Friedland, Barbara, Craig Hoesley, Marlena Gehret Plagianos, Elena Hoskin, Shimin Zhang, Natalia Teleshova, Mohcine Alami, Lea Novak, Kyle Kleinbeck, Lauren L. Katzen, Thomas Zydowsky, José Fernández-Romero, and George W. Creasy. 2016. "A first-in-human trial of MIV-150 and zinc acetate co-formulated in a carrageenan gel: Safety, pharmacokinetics, acceptability, adherence and pharmacodynamics," Journal of Acquired Immune Deficiency Syndromes 73(5): 489–496.