Preclinical Pharmacokinetics of the Marine-Derived PDE4 Inhibitor LY104 and Its Active Metabolite M1 in Beagle Dogs Following Intravenous Infusion

LY104 (previously designated as B7) is a marine-derived, non-halogenated small molecule that acts as a highly selective phosphodiesterase-4 (PDE4) inhibitor and is currently under preclinical development for the treatment of chronic obstructive pulmonary disease (COPD). Following intravenous infusion, LY104 undergoes rapid biotransformation to its active metabolite M1. Both the parent drug and its metabolite exhibit potent anti-COPD activity and favorable safety profiles. We previously reported the comprehensive pharmacokinetic profiles of LY104 and M1 in rats. In the present study, we extended our investigation to a non-rodent species by developing and re-validating an LC-MS/MS method for the simultaneous quantification of LY104 and M1 in beagle dog plasma according to ICH M10 guidelines. Calibration curves showed excellent linearity over 20–2000 ng/mL (R2 > 0.99) for both analytes. The validated method was successfully applied to characterize the pharmacokinetics of LY104 and M1 in beagle dogs following single (0.2, 1, and 5 mg/kg) and multiple (1 mg/kg once daily for 7 days) intravenous infusions. Following a single dose, LY104 was rapidly cleared with elimination half-lives of 0.14–2.51 h, while M1 exhibited much longer half-lives of 12.37–44.95 h, indicating sustained exposure of the active metabolite. Dose-normalized AUC and Cmax did not increase proportionally with dose over the 0.2–5 mg/kg range, indicating non-linear pharmacokinetics for both analytes. No clinically relevant accumulation was observed after repeated dosing. The blood-to-plasma partition ratio of LY104 was 0.58, confirming predominant plasma distribution. These findings provide the first comprehensive pharmacokinetic characterization of LY104 and M1 in a non-rodent species, filling a critical translational gap between rodent studies and first-in-human trials, and providing essential data to support physiologically based pharmacokinetic (PBPK) modeling and clinical dose selection.