Tolerability and Pharmacokinetics of Hydronidone, an Antifibrotic Agent for Hepatic Fibrosis, after Single and Multiple Doses in Healthy Subjects: an Open-Label, Randomized, Dose-Escalating, First-in-Human Study

Background and objectives: Hydronidone is a novel pyridine derivative with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the safety, tolerability, and pharmacokinetics of hydronidone in healthy subjects. Effects of sex and food on hydronidone pharmacokinetics were also evaluated.

Methods: A randomized, dose-escalating, first-in-human study was conducted in 88 subjects. Five cohorts of 34 subjects received a single dose of hydronidone capsules at 15-120 mg, and two cohorts of 12 subjects received 90 and 120 mg of hydronidone thrice daily for 7 days, and six subjects received 60 mg of hydronidone thrice daily for 28 days to assess the safety and tolerability. In 36 subjects, hydronidone pharmacokinetics were investigated following oral administration of single (30, 60, and 120 mg) and multiple (60 mg, thrice daily) doses of hydronidone.

Results: Plasma concentrations of hydronidone and area under the concentration-time curve were found to be proportional to dose. Hydronidone was rapidly absorbed [median time to maximum plasma concentration (t _max) = 0.33-0.63 h] and cleared [terminal elimination half-life (t _1/2) = 1.72-3.10 h]. Pharmacokinetic parameters after multiple doses were similar to those after single dose. Food had a significant affect (P < 0.01) on the extent and rate of absorption. No significant sex differences were noted for pharmacokinetic variables.

Conclusion: Hydronidone was well tolerated and rapidly absorbed, and concomitant intake of food reduced rate and extent (about 20 %) of absorption in healthy volunteers. There was no accumulation following multiple doses of hydronidone. These results support a 60 mg thrice-daily regimen for management of hepatic fibrosis and further development of hydronidone (registered at ClinicalTrials.gov as ChiCTR-ONC-12002899).