title: Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers.
abstract: 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.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: Jung-Ryul
authors.initials: JR
authors.lastname: Kim
authors.forename: Hwa-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Dong-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Hyeon Joo
authors.initials: HJ
authors.lastname: Yim
authors.forename: Sung-Hack
authors.initials: SH
authors.lastname: Lee
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: 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
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C534891:LC15-0444; D009930:Organic Chemicals; D010881:Piperidones; D011743:Pyrimidines