The rational design and development of a dual chamber vaginal/rectal microbicide gel formulation for HIV prevention

Ham, Anthony S.; Nugent, Sean; Peters, Jennifer J.; Katz, David F.; Shelter, Cory M.; Dezzutti, Charlene S.; Boczar, Ashlee D.; Buckheit, Karen W.; Buckheit, Robert W.

doi:10.1016/j.antiviral.2015.06.010

Cited by 23 publications

(26 citation statements)

References 45 publications

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“…The median IQP-0528 concentrations observed in the vaginal compartment are up to 7 orders of magnitude higher than the in vitro EC 50 (0.21 ng/ml to 1.29 ng/ml in human PBMCs challenged with CCR5-tropic virus subtypes A to G in the presence of IQB3002) (22). Similarly, these concentrations are also above the EC 50 of IQB3002 in the presence of simulated vaginal fluid in vitro (22). Furthermore, the median drug levels in vaginal tissues exceed the lowest concentration (10 M [3,400 ng/ml]) at which IQB3002 was previously shown to protect human ectocervical explant tissues from HIV-1 ex vivo (22) and are at levels that would be potentially inhibitory to HIV-1 infection.…”

Section: Discussionmentioning

confidence: 75%

“…Nonetheless, the IQP-0528 levels described above were observed in proximal, medial, and distal sites relative to the cervix, suggesting that the effective distribution of IQP-0528 can be achieved with a 1.5-ml volume of IQB3002 gel in RM. The median IQP-0528 concentrations observed in the vaginal compartment are up to 7 orders of magnitude higher than the in vitro EC 50 (0.21 ng/ml to 1.29 ng/ml in human PBMCs challenged with CCR5-tropic virus subtypes A to G in the presence of IQB3002) (22). Similarly, these concentrations are also above the EC 50 of IQB3002 in the presence of simulated vaginal fluid in vitro (22).…”

Section: Discussionmentioning

confidence: 91%

“…From a user acceptability perspective, a single product for both compartments is more convenient and cost-effective than two separate products. To achieve this, previously developed vaginal microbicide gels (20,21) were modified to produce a dual-chamber (vaginal and/or rectal application) microbicide gel, IQB3002, which is compatible with the release and stability of the active pharmaceutical ingredient (API), IQP-0528 (22). The IQP-0528 compound has a high therapeutic index (Ͼ1 million) (23), and the IQB3002 formulation has been shown to have no detectable cytotoxicity to vaginal and rectal cell lines and no toxic effects on the integrity and viability of ectocervical and colorectal tissue explants over a 24-h exposure period (22).…”

mentioning

confidence: 99%

“…The IQP-0528 compound has a high therapeutic index (Ͼ1 million) (23), and the IQB3002 formulation has been shown to have no detectable cytotoxicity to vaginal and rectal cell lines and no toxic effects on the integrity and viability of ectocervical and colorectal tissue explants over a 24-h exposure period (22). Normal vaginal microflora (lactobacilli) were also shown to be unaffected (22). IQP-0528 is a small molecule pyrimidinedione that potently inhibits the replication of a wide range of laboratory and clinical isolates of HIV (24)(25)(26) and has been shown to have a low 90% inhibitory concentration (IC 90 ) in both cell-based and explant tissue models (0.43 M [146 ng/ ml] in JT-CCR5 cells treated with IQP-0528 in vitro; 10.1 M [3,440 ng/ml] in JT-CCR5 cells cocultured with human ectocervical explant tissue exposed to IQP-0528 ex vivo) (27).…”

mentioning

confidence: 99%

“…The results generated from the current PK/PD study of IQB3002 gel containing 1% IQP-0528 will inform and benefit future nonnucleoside reverse transcriptase inhibitor (NNRTI) trials that rely heavily on frozen specimens for PD analysis. (22). The product was stored at room temperature (25°C) in a moisture-free environment until use.…”

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confidence: 99%

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Pharmacokinetic and Pharmacodynamic Evaluation following Vaginal Application of IQB3002, a Dual-Chamber Microbicide Gel Containing the Nonnucleoside Reverse Transcriptase Inhibitor IQP-0528 in Rhesus Macaques

Pereira¹,

Mesquita

Ham

et al. 2016

Antimicrob Agents Chemother

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fWe evaluated the in vivo pharmacokinetics and used a complementary ex vivo coculture assay to determine the pharmacodynamics of IQB3002 gel containing 1% IQP-0528, a nonnucleoside reverse transcriptase inhibitor (NNRTI), in rhesus macaques (RM). The gel (1.5 ml) was applied vaginally to 6 simian-human immunodeficiency (SHIV)-positive female RM. Blood, vaginal fluids, and rectal fluids were collected at 0, 1, 2, and 4 h. RM were euthanized at 4 h, and vaginal, cervical, rectal, and regional lymph node tissues were harvested. Anti-human immunodeficiency virus (HIV) activity was evaluated ex vivo by coculturing fresh or frozen vaginal tissues with activated human peripheral blood mononuclear cells (PBMCs) and measuring the p24 levels for 10 days after an HIV-1 Ba-L challenge. The median levels of IQP-0528, determined using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods, were between 10 4 and 10 5 ng/g in vaginal and cervical tissue, between 10 3 and 10 4 ng/g in rectal tissues, and between 10 5 and 10 7 ng/ml in vaginal fluids over the 4-h period. The vaginal tissues protected the cocultured PBMCs from HIV-1 infection ex vivo, with a viral inhibition range of 81 to 100% in fresh and frozen tissues that were proximal, medial, and distal relative to the cervix. No viral inhibition was detected in untreated baseline tissues. Collectively, the median drug levels observed were 5 to 7 logs higher than the in vitro 50% effective concentration (EC 50 ) range (0.21 ng/ml to 1.29 ng/ml), suggesting that 1.5 ml of the gel delivers IQP-0528 throughout the RM vaginal compartment at levels that are highly inhibitory to HIV-1. Importantly, antiviral activity was observed in both fresh and frozen vaginal tissues, broadening the scope of the ex vivo coculture model for future NNRTI efficacy studies. HIV-1 microbicide clinical trials have primarily been focused on vaginal gels as a topical preexposure prophylaxis (PrEP) modality to prevent virus acquisition through vaginal intercourse in at-risk women. However, several behavioral studies and clinical trial reports have shown that women also engage in unprotected receptive anal intercourse (RAI), with the highest rates of RAI being found among female sex workers and patients at sexually transmitted infection clinics (1-9). In addition, a recent metaanalysis demonstrated that the estimated per-act human immunodeficiency (HIV) transmission risk (per 10,000 exposures) for RAI is 138, compared to 11, 8, and 4 for insertive anal intercourse, receptive penile-vaginal intercourse, and insertive penile-vaginal intercourse, respectively (10). The risk of HIV acquisition via unprotected RAI may be further exacerbated through the improper use of vaginal microbicide gels or high osmolality personal lubricants in the rectal compartment, which have been shown to cause cellular inflammation and epithelial damage (11-19). These studies collectively highlight a need for a microbicide formulation that is specifically designed for safe application in both the vaginal and rectal comp...

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 91%