Pharmacokinetics and pharmacodynamics of LC15‐0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The importance of efficient drug development using biomarkers has been increasingly emphasized, from preclinical studies to clinical trials. • However, as yet few ‘validated’ or ‘qualified’ biomarkers are used in early‐stage drug development in terms of cli...

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Published in:British journal of clinical pharmacology 2009-12, Vol.68 (6), p.883-890
Main Authors: Lim, Kyoung Soo, Cho, Joo‐Youn, Kim, Bo‐Hyung, Kim, Jung‐Ryul, Kim, Hwa‐Sook, Kim, Dong‐Kyu, Kim, Sung‐Ho, Yim, Hyeon Joo, Lee, Sung‐Hack, Shin, Sang‐Goo, Jang, In‐Jin, Yu, Kyung‐Sang
Format: Article
Language:English
Subjects:
Administration, Oral
Adult
Area Under Curve
biomarker
Dipeptidyl-Peptidase IV Inhibitors - administration & dosage
Dipeptidyl-Peptidase IV Inhibitors - pharmacokinetics
Dose-Response Relationship, Drug
Double-Blind Method
DPP IV
Humans
Korea
LC15‐0444
Male
Metabolic Clearance Rate
Organic Chemicals - administration & dosage
Organic Chemicals - pharmacokinetics
Organic Chemicals - pharmacology
pharmacodynamics
pharmacokinetics
Piperidones
Pyrimidines
Themed section: Obesity
Young Adult
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Summary:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The importance of efficient drug development using biomarkers has been increasingly emphasized, from preclinical studies to clinical trials. • However, as yet few ‘validated’ or ‘qualified’ biomarkers are used in early‐stage drug development in terms of clinical pharmacology and disease pathophysiology. WHAT THIS STUDY ADDS • This first‐time‐in‐human study provides evidence of the pharmacological activity of LC15‐0444 in humans, by using dipeptidyl peptidase IV activity and active glucagon‐like peptide‐1 concentrations. • LC15‐0444 possesses pharmacokinetic and pharmacodynamic characteristics that support a once‐daily dosing regimen. AIMS LC15‐0444 is a selective and competitive inhibitor of dipeptidyl peptidase (DPP) IV with potential for the treatment of Type 2 diabetes. The aim was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles after multiple oral ascending doses of LC15‐0444 in healthy male subjects. METHODS A dose block‐randomized, double‐blind, placebo‐controlled, parallel group study was performed in three groups with 10 subjects (eight for active drug; two for placebo) per group; each group received 200, 400 or 600 mg of LC15‐0444 once daily for 10 days. Blood and urine samples were collected up to 24 h after the first dosing and up to 72 h after the last dosing. RESULTS The LC15‐0444 concentration–time profiles exhibited characteristics of multicompartment disposition. No dose‐ or time‐dependent change in PK parameters was observed. Mean elimination half‐life was in a range 16.6–20.1 h in the dose groups. Mean renal clearance and fraction of unchanged drug excreted in urine was 18.6–21.9 and 0.40–0.48 l h−1, respectively. In the steady state, mean accumulation ratios by dose groups were between 1.22 and 1.31. More than 80% inhibition of DPP IV activity from baseline was sustained for >24 h in all dose groups. CONCLUSIONS This study provides evidence of the pharmacological activity of LC15‐0444 in humans. LC15‐0444 possesses PK and PD characteristics that support a once‐daily dosing regimen.
ISSN:0306-5251
1365-2125
DOI:10.1111/j.1365-2125.2009.03376.x