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 h 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 t1/2based 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 approximately 2 hours. Minimal accumulation of VNRX‑5133 was observed following q8h dosing over 10 days.In the SAD phase, AEs occurred in 4 subjects (33.3%) with placebo and 7 (19.4%) with VNRX-5133. In the MAD phase, AEs occurred in 3 subjects (33.3%) with placebo and 8 (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 to 1500 mg and multiple doses of 250 to 750 mg q8h, VNRX-5133 demonstrated a linear and dose-proportional PK profile with low variability. No safety issues were identified.
VenatoRx Pharmaceuticals, Inc.:
D. Dickerson, VenatoRx Pharmaceuticals, Inc.: Research Contractor , Research support .
T. Henkel, VenatoRx Pharmaceuticals, Inc.: Employee , Salary .