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Jan & 27 - 28
Feb 3 & 4 - 2021
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Higher Rectal Penetration Needed With PC-1005 Microbicide Gel
  HIVR4P Virtual, January 27-28 and February 3-4, 2021
Mark Mascolini
A triple-agent rectal microbicide gel aiming to prevent HIV, HSV, and HPV infection yielded rectal tissue concentrations below the 100 ng/g target for HIV, and the antiretroviral used could not be detected in vaginal fluids [1]. Microbicide Trials Network (MTN) researchers concluded that they need a longer-acting reformulation that delivers more product to rectal tissues.
MTN-037 is a phase 1 dose-escalation study of PC-1005 gel, which contains 0.002% MIV-150, 0.3% zinc acetate, and 3.0% carrageenan [2]. MIV-150 is a nonnucleoside reverse transcriptase inhibitor. Previous work found that MIV-150 in carrageenan reduced vaginal SIV infection rates and rectal sHIV transmission in macaques [3]. The first-in-human trial of MIV-150 and zinc acetate coformulated in carrageenan found that 7 of 7 cervicovaginal lavage samples had activity against HIV and HPV 4 hours after dosing [4].
In the new phase 1 trial, the 13 HIV-negative study participants were 18 or older (median age 34). Six were white, 5 black, and 2 mixed race; 7 were men and 6 women. Twelve of 13 people completed all doses. The trial took place at the University of Alabama and the University of Pittsburgh. Each participant received 3 rectal gel doses of PC-1005 at increasing volumes of 4, 16, and 32 mL, with a washout between doses. Researchers collected plasma samples, rectal tissue and fluid, and vaginal fluid 1, 2, 3, 4, 5-6, 24, and 48 hours after dosing.
No one had grade 3 or 4 adverse events. Three grade 2 adverse events were not related to study drug. Five of 10 grade 1 events were related to study drug. Across the three dose volumes, 83% to 92% of study participants rated the gel comfortable or very comfortable.
With dose volumes of 4, 16, and 32 mL, median plasma MIV-150 levels peaked 1 to 2 hours after dosing at 0.074 ng/mL, 0.184 ng/mL, and 0.171 ng/mL respectively. Median concentrations lay below assay quantitation limits 24 hours after dosing. Median MV-150 half-life ranged from 1.4 to 1.9 hours across doses. MIV-150 peak concentration and area under the concentration-time curve (AUC) suggested saturated absorption, that is, the concentration increase with increasing gel volume was less than dose-proportional.
MIV-150 concentrations in rectal tissue peaked 0.5 to 1 hour after dosing at 1.4 ng/g at 4 mL gel volume, 46.0 ng/g at 16 mL, and at 79.7 ng/g at 32 mL-all well below the 100-ng/g target. Again, peaks were not dose-proportional. Most measurements lay below the limit of quantitation 24 hours after dosing. Vaginal fluid levels were all below the limit of quantitation.
Rectal fluid MIV-150 concentration peaked 0.5 to 3 hours after dosing and fell rapidly over 24 hours. MIV-150 rectal fluid levels lay below the limit of quantitation for 5 of 9 samples at 24 hours. All cervicovaginal fluid samples were below the limit of quantitation. Ex vivo HIV explant challenge data showed minimal protection from HIV.
1. Ho K, Hoesley C, Anderson P, et al. 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). HIVR4P (HIV Research for Prevention) Virtual, January 27-28 and February 3-4, 2021. Abstract OA16.04.
2. Microbicide Trials Network. MTN-037 protocols. https://mtnstopshiv.org/research/studies/mtn-037/mtn-037-protocols 3. Singer R, Derby N, Rodriguez A, et al. The nonnucleoside reverse transcriptase prevents rectal transmission of simian/human immunodeficiency virus infection in minhibitor MIV-150 in carrageenan gel acaques. J Virol. 2011;85:5504-5512. doi: 10.1128/JVI.02422-10.
4. Friedland BA, Hoesley CJ, Plagianos M, et al. First-in-human trial of MIV-150 and zinc acetate coformulated in a carrageenan gel: safety, pharmacokinetics, acceptability, adherence, and pharmacodynamics. J Acquir Immune Defic Syndr. 2016;73:489-496. doi: 0.1097/QAI.0000000000001136.