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Abstract
Background: LC15-0444 is a selective inhibitor of dipeptidyl peptidase (DPP) IV under investigation
in Korea for the treatment of type 2 diabetes.
Objective: The aim of this study was to investigate the pharmacokinetic (PK), pharmacodynamic
(PD), and tolerability profiles of a single dose of LC15-0444 in healthy male subjects.
Methods: A dose—block-randomized, double-blind, placebo-controlled, ascending single-dose,
Phase I study was performed in healthy Korean male subjects assigned to receive 25,
50, 100, 200, 400, or 600 mg of LC15-0444 capsules. Blood and urine samples were collected
up to 72 hours after administration. Plasma and urine drug concentrations were determined
by tandem mass spectrometry coupled with high-performance liquid chromatography. DPP
IV activity was measured by continuous spectrophotometric assay. An additional food
effect study was performed in the 100-mg dose group; changes in PK and PD parameters
after highfat diet were evaluated. Adverse events (AEs) were detected through investigator
inquiries, spontaneous reports, and clinical evaluations such as physical examinations,
vital sign measurements, 12-lead electrocardiography, clinical laboratory tests (eg,
hematology, blood chemistry, coagulation, urinalysis), and computerized impedance
cardiography.
Results: Sixty Korean men (mean age, 25.3 years [range, 19-39 years]; weight, 68.3 kg [range,
53.6-84.9 kg]) were enrolled, providing 10 subjects for each dose group. After administration,
LC15-0444 reached Tmax at 0.5 to 5.1 hours, and was eliminated with a t½ of 16.7 to 21.3 hours. The mean fraction of unchanged drug excreted in urine ranged
from 0.21 to 0.34 and mean renal clearance was 15.5 to 23.6 L/h. The dose-normalized
AUC exhibited dose-linearity over the range of 50 to 400 mg. All doses of LC15-0444
=200 mg were found to inhibit 80% of DPP IV activity for 24 hours. High-fat diet did
not significantly influence the AUC of LC15-0444. LC15-0444 was generally well tolerated.
None of the subjects developed any serious clinical or laboratory AEs or discontinued
the study due to an AE. All AEs were mild or moderate, and no dose-related trends
were observed. Fortysix AEs were reported in 18 subjects (30.0%). AEs considered to
be related to the study drug were headache (6 cases), dizziness (2), nausea (1), epistaxis
(1), and increased heart rate (1). All AEs resolved spontaneously.
Conclusions: A single dose of LC15-0444 exhibited linear PK properties over the range of 50 to
400 mg in these healthy Korean male subjects. PK characteristics were not significantly
influenced by food. In addition, doses ≥200 mg of LC15-0444 inhibited plasma DPP IV
activity by >80% over a 24-hour dosing interval, and a 600-mg dose increased active
glucagon-like peptide-1 levels after a standardized meal. LC15-0444 was generally
well tolerated.
Key words:
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Article info
Publication history
Accepted:
February 18,
2008
Footnotes
Data from this study were presented in poster form at the 109th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, April 2-5, 2008, Orlando, Florida. An abstract has been published in Clin Pharmacol Ther. 2008;83(Suppl1):S88.
Identification
Copyright
© 2008 Excerpta Medica Inc. All rights reserved. Published by Elsevier Inc.
