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

Yutaka Takeuchi, Masayuki Namiki, Yasumi Kitahara, Setsuo Hasegawa, Akihiro Ohnishi, Nobuyuki Yasuda, Takashi Inoue, Richard Clark, Kazuto Yamazaki

Clinical Development, Japan/Asia Clinical Research PCU, Eisai Co., Ltd., Tokyo, Japan.
Clinical Development, Japan/Asia Clinical Research PCU, Eisai Co., Ltd., Tokyo, Japan;.
Clinical Pharmacology, Clinical Science, SOCS CFU, Eisai Co., Ltd., Tokyo, Japan;.
Department of Laboratory Medicine, Daisan Hospital, Jikei University School of Medicine, Tokyo, Japan;.
Sekino Clinical Pharmacology Clinic, Tokyo, Japan; Present Address: Pharmaspur, Inc., Tokyo, Japan;.
Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan..

DOI: 10.4236/pp.2013.49093                

Abstract

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 t_max values ranging between 0.33 and 3 h after dosing. The mean t_1/2 ranged from 5.34 to 11.68 h. AUC_0-inf and C_max increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an I_max 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.

 

Keywords

Dipeptidyl Peptidase-IV Inhibitor; Rash; Histamine; Structure-Activity Relationship

Conflicts of Interest

The authors declare no conflicts of interest.

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