Safety, tolerability, and pharmacokinetics of the novel pan-phosphodiesterase inhibitor ZSP1601 in healthy subjects: a double-blinded, placebo-controlled first-in-human single-dose and multiple-dose escalation and food effect study

Abstract

ABSTRACT Background: The pharmacokinetics (PK), safety, and tolerability profiles of ZSP1601, a first-in-class pan-phosphodiesterase (PDE) inhibitor, were evaluated in healthy Chinese volunteers. Research design and methods: This Phase 1a study consisted of a double-blinded, randomized, placebo-controlled single ascending dose (SAD) (25 to 350 mg), multiple ascending doses (MAD) (50 or 100 mg QD), and a two-period crossover food effect study (100 mg). Results: ZSP1601 was quickly absorbed, with maximum plasma concentrations (Cmax) reached at 1.25 to 2.50 h (median Tmax). The exposures exhibited dose-proportional increases, while the mean half-life (t1/2) ranged from 6.34–8.64 h. Steady-state was reached within seven days in the MAD study. The mean steady trough concentrations were 423 and 588 ng/mL, respectively. ZSP1601 accumulation was low, with ratios ≤ 1.5. The bioavailability of ZSP1601 was equivalent under fasted and fed states. All adverse events (AEs) were assessed as mild or moderate, with headaches as the most common. The highest single doses (275 and 350 mg) yielded more AEs, yet the rates were similar with the placebo cohorts in the MAD study. Conclusions: The safety and PK profiles of ZSP1601 support further efficacy evaluation in nonalcoholic steatohepatitis patients. Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03392779).