Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers
Article first published online: 2 FEB 2009
© 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 68, Issue 6, pages 883–890, December 2009
How to Cite
Lim, K. S., Cho, J.-Y., Kim, B.-H., Kim, J.-R., Kim, H.-S., Kim, D.-K., Kim, S.-H., Yim, H. J., Lee, S.-H., Shin, S.-G., Jang, I.-J. and Yu, K.-S. (2009), Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers. British Journal of Clinical Pharmacology, 68: 883–890. doi: 10.1111/j.1365-2125.2009.03376.x
- Issue published online: 27 NOV 2009
- Article first published online: 2 FEB 2009
- Received 14 May 2008 Accepted8 January 2009
- DPP IV;
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.