A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol.

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-PEG4-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG4-Chol. Pre-clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG4-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.

SUBMITTER: Quinn K 

PROVIDER: S-EPMC5572697 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature