Journal Article

First-in-human safety and pharmacokinetics (PK) of a MIV-150/zinc acetate/carrageenan gel (PC-1005)

Background
The candidate microbicide, PC-1005, completely protects Depo-Provera-treated macaques from a single vaginal SHIV-RT challenge 8 h post dose, and significantly reduces HPV and HSV-2 infection in murine models. PC-1005 contains 50 μM MIV-150 (NNRTI) and 14 mM zinc acetate dihydrate in a carrageenan gel.

Methods
In preparation for a Phase 1 trial, an open-label, safety run-in was conducted at the University of Alabama at Birmingham to assess the safety and pharmacokinetics (PK) of PC-1005. Healthy, sexually-abstinent, HIV and Hepatitis B/C negative, STI-free, non-pregnant women aged 19–49 on effective contraception, were eligible. Under clinical supervision, women inserted 4 ml of PC-1005 once daily for 3 days. Evaluations included physical exam, pelvic exam with colposcopy, EKG, vitals, and safety labs. Blood was drawn for PK assessment at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 h post-doses 1 and 3; and 48 h and 72 h post-dose 3.

Results
From June-July 2014, 5 women (2 Black, 2 White, 1 Native American) completed the study (3 doses). Median age was 29 (range 29–38). Three women reported 4 possibly-related AEs; 3 were DAIDS Grade 1: vaginal discharge, intermenstrual bleeding, lower abdominal pressure; 1 was DAIDS Grade 2: vaginal itching. Safety labs, physical exams, vital signs, and colposcopy were all normal or not considered clinically significant by investigators. All subjects had detectable MIV-150 blood levels after dosing; no accumulation was noted. On Day 3, the median (and range) of MIV-150 PK parameters were: T_1/2 of 4.98 h (3.08–6.55); C_max of 77.4 pg/ml (55.25–166.85); T_max of 4 h (2–6); AUC_last of 774.38 pg h/ml (622.14–1188.66); AUC_inf of 803.23 pg h/ml (684.82–1252). There was no increase in zinc blood levels from baseline; median C_max of zinc was 79 μg/ml (58–94) on Day 3.

Conclusions
PC-1005 was well tolerated after 3 days of dosing in 5 healthy women. MIV-150 was absorbed with low levels observed systemically; no accumulation was noted. Zinc levels were unchanged from baseline.