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A first-in-human study of the novel HIV-fusion inhibitor C34-PEG-Chol
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Quinn, Killian, Traboni, Cinzia, Penchala, Sujan Dily, Bouliotis, Georgios, Doyle, Nicki, Libri, Vincenzo, Khoo, Saye, Ashby, Deborah, Weber, Jonathan, Nicosia, Alfredo, Cortese, Riccardo, Pessi, Antonello and Winston, Alan (2017) A first-in-human study of the novel HIV-fusion inhibitor C34-PEG-Chol. Scientific Reports, 7 (1). 9447. doi:10.1038/s41598-017-09230-0
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WRAP-first-in-human-study-novel-HIV-fusion-inhibitor-C34-PEG-Chol-Bouliotis-2019.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (1164Kb) | Preview |
Official URL: https://doi.org/10.1038/s41598-017-09230-0
Abstract
Long-acting injectable antiretroviral (LA-ARV) drugs with low toxicity profiles and propensity for drug-drug interactions are a goal for future ARV regimens. C34-PEG-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG-Chol. Pre-clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG-Chol at incrementing doses or placebo. Detailed clinical (including injection site reaction (ISR) grading), plasma pharmacokinetic (time-to-minimum-effective-concentration (MEC, 25 ng/mL) and pharmacodynamic (plasma HIV RNA) parameters were assessed. In both mice and dogs, no-observed-adverse effect level (NOAEL) was observed at a 12 mg/kg/dose after two weeks. Of 5 men enrolled, 3 received active drug (10 mg, 10 mg and 20 mg). In 2 individuals grade 3 ISR occurred and the study was halted. Both ISR emerged within 12 hours of active drug dosing. No systemic toxicities were observed. The time-to-MEC was >72 and >96 hours after 10 and 20 mg dose, respectively, and mean change in HIV RNA was -0.9 log10 copies/mL. These human pharmacodynamic and pharmacokinetic data, although limited to 3 subjects, of C34-PEG-4-Chol suggest continuing evaluation of this agent as a LA-ARV. However, alternative administration routes must be explored.
| Item Type: | Journal Article | |||||||||
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| Subjects: | R Medicine > RA Public aspects of medicine R Medicine > RC Internal medicine |
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| Divisions: | Faculty of Medicine > Warwick Medical School > Health Sciences > Clinical Trials Unit Faculty of Medicine > Warwick Medical School > Health Sciences Faculty of Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | HIV infections -- Chemotherapy, Antiretroviral agents | |||||||||
| Journal or Publication Title: | Scientific Reports | |||||||||
| Publisher: | Nature Publishing Group | |||||||||
| ISSN: | 2045-2322 | |||||||||
| Official Date: | 25 August 2017 | |||||||||
| Dates: |
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| Date of first compliant deposit: | 10 October 2019 | |||||||||
| Volume: | 7 | |||||||||
| Number: | 1 | |||||||||
| Article Number: | 9447 | |||||||||
| DOI: | 10.1038/s41598-017-09230-0 | |||||||||
| Status: | Peer Reviewed | |||||||||
| Publication Status: | Published | |||||||||
| Access rights to Published version: | Open Access | |||||||||
| RIOXX Funder/Project Grant: |
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