Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers.
BACKGROUND
* 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.


CONCLUSIONS
* 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.


OBJECTIVE
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.
Lim
Kyoung Soo
KS
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Cho
Joo-Youn
JY
Kim
Bo-Hyung
BH
Kim
Jung-Ryul
JR
Kim
Hwa-Sook
HS
Kim
Dong-Kyu
DK
Kim
Sung-Ho
SH
Yim
Hyeon Joo
HJ
Lee
Sung-Hack
SH
Shin
Sang-Goo
SG
Jang
In-Jin
IJ
Yu
Kyung-Sang
KS
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007723:Korea; D008297:Male; D008657:Metabolic Clearance Rate; D009930:Organic Chemicals / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010881:Piperidones; D011743:Pyrimidines; D055815:Young Adult
D054873:Dipeptidyl-Peptidase IV Inhibitors; C534891:LC15-0444; D009930:Organic Chemicals; D010881:Piperidones; D011743:Pyrimidines