Safety, Tolerability, and Pharmacokinetics of E3030, a Novel Peroxisome Proliferator-Activated Receptor <i>α/γ</i>Dual Agonist, in Healthy Japanese Male Subjects

Objective: The objectives of the present study were to evaluate the safety of single oral dose E3030 in healthy Japanese male subjects, and to evaluate pharmacokinetics after single oral dose E3030 and food effect on pharmacokinetic profiles. Methods: This study was conducted in a randomized, double-blind, placebo-controlled, ascending single-dose study in 56 healthy Japanese male subjects. Subjects were orally administered E3030 (0.5-40 mg) or placebo. Results: Six of 42 (14%) subjects’ administered E3030 experienced adverse events;however, all adverse events were mild and transient, and there was no dose-dependent increase in any adverse event. Plasma samples were collected over 96 hours after dosing. After administration in the fasted state, Cmax of E3030 was achieved between 1.00 and 1.75 hours, indicating rapid absorption. Both Cmax and AUC were dose-proportional in the range of 0.5 to 40 mg. The average range of elimination half-life was 18.4-23.8 hr. CL/F and Vz/F also remained nearly constant regardless of dose levels. In addition, food effect was exploratorily evaluated in five subjects of administered E3030 (10 mg) in both fasted and fed states. The fed/fasted ratios for the geometric mean of the Cmax and AUC were 0.803 and 0.913, respectively. Conclusion: E3030 was safe and well tolerated at single doses up to 40 mg. The pharmacokinetic profile showed good linearity, and food effect on pharmacokinetics of E3030 was not significant.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of E3024, a Novel and Selective Dipeptidyl Peptidase-IV Inhibitor, in Healthy Japanese Male Subjects: Rash Development in Men and Its Possible Mechanism

E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.