Article date: December 2009
By: Kyoung Soo Lim, Joo‐Youn Cho, Bo‐Hyung Kim, Jung‐Ryul Kim, Hwa‐Sook Kim, Dong‐Kyu Kim, Sung‐Ho Kim, Hyeon Joo Yim, Sung‐Hack Lee, Sang‐Goo Shin, In‐Jin Jang, Kyung‐Sang Yu, in Volume 68, Issue 6, pages 883-890
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.
DOI: 10.1111/j.1365-2125.2009.03376.x
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