1401. A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Pharmacokinetics of Single and Repeat Doses of VNRX-5133 in Healthy Subjects

BACKGROUND: VNRX-5133 is a novel, non-β-lactam, β-lactamase inhibitor with potent and selective direct inhibitory activity against serine- and metallo-β-lactamases. VNRX-5133, combined with the β-lactam antibiotic cefepime, is being developed for the treatment of serious infections due to multidrug-resistant Gram-negative bacteria, including ESBL-producing organisms and carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. This study evaluated the safety and pharmacokinetics (PK) of VNRX-5133 after single and multiple intravenous (IV) doses. METHODS: This was a Phase 1, randomized, single-center, double-blind, placebo-controlled, sequential group study in healthy subjects. In a single ascending dose (SAD), phase subjects received 62.5, 125, 250, 500, 1000, and 1500 mg VNRX-5133 via a 2-hour IV infusion. In a multiple ascending dose (MAD) phase, subjects received 250, 500, and 750 mg VNRX-5133 q8h for 10 days. PK samples were collected predose and at frequent intervals. Safety was assessed from adverse events (AEs), laboratory tests, physical examination, vital signs, and electrocardiogram (ECG). RESULTS: All subjects completed the SAD (n = 48) and the MAD phases (n = 36). VNRX-5133 plasma exposure exhibited dose proportionality and linearity. Total clearance (CL) was ~6 L/h and volume of distribution (Vz) was ~30 to 50 L. The t(1/2) based on a noncompartmental analysis was ~6.5 hours. Modeling of VNRX-5133 plasma concentrations showed that the PK fit a 2-compartment model with most of the drug exposure accounted for within the initial phase of ~2 hours. Minimal accumulation of VNRX-5133 was observed following q8h dosing over 10 days. In the SAD phase, AEs occurred in four subjects (33.3%) with placebo and seven (19.4%) with VNRX-5133. In the MAD phase, AEs occurred in three subjects (33.3%) with placebo and eight (29.6%) with VNRX-5133. The most common AEs with VNRX-5133 were headache (11.1%), nausea (7.4%), and constipation (7.4%). CONCLUSION: After single doses of 62.5–1,500 mg and multiple doses of 250–750 mg q8h, VNRX-5133 demonstrated a linear and dose-proportional PK profile with low variability. No safety issues were identified. DISCLOSURES: B. Geibel, VenatoRx Pharmaceuticals, Inc.: Employee, Salary. J. Dowell, VenatoRx Pharmaceuticals, Inc.: Consultant, Consulting fee. D. Dickerson, VenatoRx Pharmaceuticals, Inc.: Research Contractor, Research support. T. Henkel, VenatoRx Pharmaceuticals, Inc.: Employee, Salary