Phase 1 safety and pharmacokinetic study of candidate rectal microbicide PC-1005 rectal gel (MIV-150/zinc acetate /carrageenan) in HIV-1 seronegative adults (MTN-037)


BACKGROUND: On demand topical PrEP may meet the needs of those who prefer episodic, non-systemic PrEP or struggle with or reject daily oral PrEP. PC-1005 gel, which contains MIV-150, is active against HIV-1, HPV, and HSV-2 - an attractive multipurpose prevention technology candidate. We evaluated rectal safety and pharmacokinetics (PK) of PC-1005 gel applied rectally.
METHODS: HIV-uninfected persons >18 years of age each received a series of 3 rectal gel doses at increasing volumes of 4, 16, and 32 mL with a washout period between doses. Following each dose, plasma, rectal tissue and fluid, and vaginal fluid were collected up to 7 times over 48 hours.
RESULTS: We enrolled 13 participants, 7 men and 6 women (birth sex), median 34 years of age, including 6 white, 5 black, and 2 mixed race/ethnicity. 12 participants completed all 3 doses.
Thirteen adverse events were reported, all Grade 1 or 2, of which 5 were judged related to study drug without relationship to dose volume. Median (interquartile range) plasma MIV-150 concentration peaked 1 or 2 hours after dosing at 0.074 ng/mL (0.052, 0.086), 0.184 (0.162, 0.211), and 0.171 (0.098, 0.316), after 4, 16, and 32 mL doses, respectively; median concentrations were below assay quantitation limits (BLQ) 24 hours after dosing. Median half-life was 1.4-1.9 hours across dose volumes.Rectal Tissue MIV-150 peaked 0.5-1 hours after dosing at 1.4 ng/g (ng/mL) (0.8, 1.9), 46.0 (30.7, 831.0), and 79.7 (11.9, 116.0), respectively, after each dose volume. Median tissue concentrations were BLQ (0.7 ng/g) at 1.5-3, 24, and 3.5-5 hours after each escalating dose volume, respectively. Median rectal fluid concentrations were >14 ng/mL (ng/g) through 5 hours in all arms; vaginal fluid samples were all BLQ (0.2 ng/mL). Across dose volumes, 83%-92% of participants rated the gel as comfortable or very comfortable.
CONCLUSIONS: PC-1005 gel was well-tolerated with low systemic exposure. MIV-150 rectal tissue concentrations were transient and below the 100 ng/g target; no MIV-150 was detectable in vaginal fluids. Based on concentration data, a longer-acting reformulation delivering more MIV-150 to rectal tissues is likely needed to support further development of PC-1005 as an on demand HIV rectal microbicide.