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

Abstract

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.

Figure 1

Mean plasma concentration–time profiles of LC15-0444. Data are presented as mean ± SD. 200 mg (N = 8) (—•—); 400 mg (N = 8) (—▵—); 600 mg (N = 8) ()

Figure 2

Linear regressions of LC15-0444 pharmacokinetic parameters after multiple oral administrations of 200, 400 or 600 mg to subjects. Left, C_max,ssvs. dose; right, AUC_ss,τvs. dose. Regression line (——); 95% Confidence interval (········)

Figure 3

Inhibition from baseline plasma dipeptidyl peptidase IV activity–time profiles during multiple oral administrations of LC15-0444. Data are presented as mean ± SE. Placebo (N = 6) (—⋆—); 200 mg (N = 8) (); 400 mg (N = 8) (—▵—); 600 mg (N = 8) ()

Figure 4

Weighted average plasma concentrations of active glucagon-like peptide-1 by dose groups after single and multiple oral administrations of LC15-0444. Data are presented as mean ± SE. *P < 0.05, †P < 0.01, ‡P < 0.001 compared with placebo, using Dunnett's test. Placebo (N = 6) (); 200 mg (N = 8) (); 400 mg (N = 8) (); 600 mg (N = 8) ()