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

Authors

  • Kyoung Soo Lim,

    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital and Clinical Development, LG Life Sciences Ltd., Seoul and
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  • Joo-Youn Cho,

    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital and Clinical Development, LG Life Sciences Ltd., Seoul and
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  • Bo-Hyung Kim,

    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital and Clinical Development, LG Life Sciences Ltd., Seoul and
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  • Jung-Ryul Kim,

    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital and Clinical Development, LG Life Sciences Ltd., Seoul and
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  • Hwa-Sook Kim,

    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital and Clinical Development, LG Life Sciences Ltd., Seoul and
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  • Dong-Kyu Kim,

    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital and Clinical Development, LG Life Sciences Ltd., Seoul and
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  • Sung-Ho Kim,

    1. Research & Development Park, LG Life Sciences Ltd., Daejeon, Korea
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  • Hyeon Joo Yim,

    1. Research & Development Park, LG Life Sciences Ltd., Daejeon, Korea
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  • Sung-Hack Lee,

    1. Research & Development Park, LG Life Sciences Ltd., Daejeon, Korea
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  • Sang-Goo Shin,

    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital and Clinical Development, LG Life Sciences Ltd., Seoul and
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  • In-Jin Jang,

    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital and Clinical Development, LG Life Sciences Ltd., Seoul and
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  • Kyung-Sang Yu

    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital and Clinical Development, LG Life Sciences Ltd., Seoul and
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Assistant Professor Kyung-Sang Yu, MD, PhD, College of Medicine, Seoul National University, Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul 110-744, Korea.
Tel: + 82 2 2072 1920
Fax: + 82 2 742 8292
E-mail: ksyu@snu.ac.kr

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.

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