%0 Journal Article
%T 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
%A Yutaka Takeuchi
%A Masayuki Namiki
%A Yasumi Kitahara
%A Setsuo Hasegawa
%A Akihiro Ohnishi
%A Nobuyuki Yasuda
%A Takashi Inoue
%A Richard Clark
%A Kazuto Yamazaki
%J Pharmacology & Pharmacy
%P 663-678
%@ 2157-9431
%D 2013
%I Scientific Research Publishing
%R 10.4236/pp.2013.49093
%X <p class=\"MsoNormal\" style=\"text-align:justify;\">
	<span lang=\"EN-US\"><span style=\"font-family:Verdana;\">E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4</span><i><span style=\"font-family:Verdana;\">H</span></i><span style=\"font-family:Verdana;\">-imidazo[4,5-</span><i><span style=\"font-family:Verdana;\">d</span></i><span style=\"font-family:Verdana;\">]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</span></span><span lang=\"EN-US\"> </span><span lang=\"EN-US\" style=\"font-family:Verdana;\">subjects
were orally administered E3024 (5, 10, 20, 40, or</span><span lang=\"EN-US\"> </span><span lang=\"EN-US\" style=\"font-family:Verdana;\">80 mg) or placebo.</span><span lang=\"EN-US\"> </span><span lang=\"EN-US\"><span style=\"font-family:Verdana;\">E3024 was rapidly absorbed, with t</span><sub><span style=\"font-family:Verdana;\">max</span></sub><span style=\"font-family:Verdana;\"> values ranging between 0.33 and 3 h after dosing. The mean t</span><sub><span style=\"font-family:Verdana;\">1/2</span></sub><span style=\"font-family:Verdana;\"> ranged
from 5.34 to 11.68 h. AUC</span><sub><span style=\"font-family:Verdana;\">0-inf</span></sub></span><span lang=\"EN-US\"> </span><span lang=\"EN-US\"><span style=\"font-family:Verdana;\">and C</span><sub><span style=\"font-family:Verdana;\">max</span></sub><span style=\"font-family:Verdana;\"> increased dose-proportionately.
PK-PD relationship of E3024 was evaluated </span></span><span lang=\"EN-US\" style=\"font-family:Verdana;\">by </span><span lang=\"EN-US\"><span style=\"font-family:Verdana;\">using an I</span><sub><span style=\"font-family:Verdana;\">max</span></sub></span><span lang=\"EN-US\"> </span><span lang=\"EN-US\"><span style=\"font-family:Verdana;\">model, indicating that plasma E3024 concentrations
and inhibitory effects of plasma DPP-IV activity were well correlated. The IC</span><sub><span style=\"font-family:Verdana;\">50</span></sub></span><span lang=\"EN-US\"> </span><span lang=\"EN-US\" style=\"font-family:Verdana;\">value was calculated as 33.7 ng/mL, which</span><span lang=\"EN-US\"> </span><span lang=\"EN-US\" style=\"font-family:Verdana;\">was</span><span lang=\"EN-US\"> </span><span lang=\"EN-US\"><span style=\"font-family:Verdana;\">consistent with </span><i><span
%K Dipeptidyl Peptidase-IV Inhibitor
%K Rash
%K Histamine
%K Structure-Activity Relationship
%U http://www.scirp.org/journal/PaperInformation.aspx?PaperID=40577