Phase Ib single- and multiple-dose pharmacokinetic study of oral NV-52 in healthy volunteers.

Background And Objective: NV-52 is a novel synthetic flavonoid thromboxane synthase (TXS) inhibitor that may be useful for the maintenance of remission in inflammatory bowel disease (IBD). This study was conducted to determine the single- and multiple-dose pharmacokinetics of NV-52 in nine healthy volunteers (five men, four women; mean [+/- SD] age 23 +/- 2 years).

Methods: NV-52 400 mg was administered once daily for 10 days (excluding day 2) in an open-label study. Plasma was sampled and urine was collected for 48 hours after the first and last doses. Plasma and urine unconjugated and total (unconjugated plus glucuronide and sulphate conjugated) NV-52 concentrations were measured using liquid chromatography-mass spectrometry.

Results: No adverse events were observed. Unconjugated and total NV-52 appeared and rose rapidly in plasma following the first dose. Time to maximum concentration values were 1.92 +/- 1.17 and 2.72 +/- 1.52 hours for unconjugated and total NV-52, respectively. Unconjugated and total NV-52 were eliminated with plasma half-lives of 13.12 +/- 17.31 and 18.03 +/- 19.06 hours, respectively, following the first dose. Pre-dose levels following multiple-dose administration were 135.17 +/- 120.03 and 751.9 +/- 679.74 ng/mL for unconjugated and total NV-52, respectively. Multiple-dose administration did not significantly alter the pharmacokinetics of NV-52. Renal elimination accounted for about 20-35% of the total (largely conjugated) drug but only 1% of unconjugated NV-52.

Conclusions: Plasma concentrations of unconjugated NV-52 following single- and multiple-dose administration were well above the range found to be associated with suppression of colitis in a murine model of IBD.