First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults.

Autor: Mammen MP; Vical Incorporated, San Diego, California, USA., Armas D; Celerion, Tempe, Arizona, USA., Hughes FH; Vical Incorporated, San Diego, California, USA., Hopkins AM; Vical Incorporated, San Diego, California, USA., Fisher CL; Vical Incorporated, San Diego, California, USA., Resch PA; Vical Incorporated, San Diego, California, USA., Rusalov D; Vical Incorporated, San Diego, California, USA., Sullivan SM; Vical Incorporated, San Diego, California, USA., Smith LR; Vical Incorporated, San Diego, California, USA molecularry@outlook.com.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2019 Oct 22; Vol. 63 (11). Date of Electronic Publication: 2019 Oct 22 (Print Publication: 2019).
DOI: 10.1128/AAC.00969-19
Abstrakt: VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal in vitro activity, and potent in vivo activity against Aspergillus fumigatus , including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study, was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (i.v.) doses of VL-2397. All dosing cohorts were fully enrolled; all subjects completed the safety follow-up. A safety committee reviewed the safety data for each dosing cohort prior to recommending the initiation of each subsequent cohort. No serious adverse events (SAEs) occurred; the majority of treatment-emergent adverse events (TEAEs) were mild and self-limited. The most common drug-related TEAEs were infusion site reactions. No clinically concerning trends were noted in vital signs, electrocardiograms, physical examinations, or safety laboratory results. Following single infusions of VL-2397, the overall and maximum exposures rose less than proportionally with increasing doses from 3 mg to 1,200 mg as indicated by area under the concentration-time curve over 24 h (AUC 24 ) and maximum concentration ( C max ). No signs of VL-2397 accumulation were observed following i.v. infusions of 300, 600, and 1,200 mg every 24 h (q24h) for 7 days. Renal elimination played a major role in total body clearance, with up to 47% of unmetabolized drug in urine 24 h after administration at single doses of >30 mg. Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK, and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis.
(Copyright © 2019 American Society for Microbiology.)
Databáze: MEDLINE
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