TITLE:
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
AUTHORS:
Yutaka Takeuchi, Masayuki Namiki, Yasumi Kitahara, Setsuo Hasegawa, Akihiro Ohnishi, Nobuyuki Yasuda, Takashi Inoue, Richard Clark, Kazuto Yamazaki
KEYWORDS:
Dipeptidyl Peptidase-IV Inhibitor; Rash; Histamine; Structure-Activity Relationship
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.4 No.9,
December
9,
2013
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 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 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.