Inhibitor Report for: Gemigliptin

Gemigliptin, a novel dipeptidyl peptidase (DPP)-4 inhibitor, is approved for use as a monotherapy or in combination therapy to treat hyperglycemia in patients with type 2 diabetes mellitus. In this study, we investigated the pharmacological profiles of gemigliptin in vitro and in vivo and compared them to those of the other DPP-4 inhibitors. Gemigliptin was a reversible and competitive inhibitor with a Ki value of 7.25+/-0.67nM. Similar potency was shown in plasma from humans, rats, dogs, and monkeys. The kinetics of DPP-4 inhibition by gemigliptin was characterized by a fast association and a slow dissociation rate compared to sitagliptin (fast on and fast off rate) or vildagliptin (slow on and slow off rate). In addition, gemigliptin showed at least >23,000-fold selectivity for DPP-4 over various proteases and peptidases, including DPP-8, DPP-9, and fibroblast activation protein (FAP)-alpha. In the rat, dog, and monkey, gemigliptin showed more potent DPP-4 inhibitory activity in vivo compared with sitagliptin. In mice and dogs, gemigliptin prevented the degradation of active glucagon-like peptide-1 by DPP-4 inhibition, which improved glucose tolerance by increasing insulin secretion and reducing glucagon secretion during an oral glucose tolerance test. The long-term anti-hyperglycemic effect of gemigliptin was evaluated in diet-induced obese mice and high-fat diet/streptozotocin-induced diabetic mice. Gemigliptin dose-dependently decreased hemoglobin A1c (HbA1c) levels and ameliorated beta-cell damage. In conclusion, gemigliptin is a potent, long-acting, and highly selective DPP-4 inhibitor and can be a safe and effective drug for the long-term treatment of type 2 diabetes.

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.

BACKGROUND: LC15-0444 is a selective inhibitor of dipeptidyl peptidase (DPP) IV under investigation in Korea for the treatment of type 2 diabetes. OBJECTIVE: The aim of this study was to investigate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of a single dose of LC15-0444 in healthy male subjects. METHODS: A dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study was performed in healthy Korean male subjects assigned to receive 25, 50, 100, 200, 400, or 600 mg of LC15-0444 capsules. Blood and urine samples were collected up to 72 hours after administration. Plasma and urine drug concentrations were determined by tandem mass spectrometry coupled with high-performance liquid chromatography. DPP IV activity was measured by continuous spectrophotometric assay. An additional food effect study was performed in the 100-mg dose group; changes in PK and PD parameters after high-fat diet were evaluated. Adverse events (AEs) were detected through investigator inquiries, spontaneous reports, and clinical evaluations such as physical examinations, vital sign measurements, 12-lead electrocardiography, clinical laboratory tests (eg, hematology, blood chemistry, coagulation, urinalysis), and computerized impedance cardiography. RESULTS: Sixty Korean men (mean age, 25.3 years [range, 19-39 years]; weight, 68.3 kg [range, 53.6-84.9 kg]) were enrolled, providing 10 subjects for each dose group. After administration, LC15-0444 reached T(max) at 0.5 to 5.1 hours, and was eliminated with a t((1/2)) of 16.7 to 21.3 hours. The mean fraction of unchanged drug excreted in urine ranged from 0.21 to 0.34 and mean renal clearance was 15.5 to 23.6 L/h. The dose-normalized AUC exhibited dose-linearity over the range of 50 to 400 mg. All doses of LC15-0444 =200 mg were found to inhibit 80% of DPP IV activity for 24 hours. High-fat diet did not significantly influence the AUC of LC15-0444. LC15-0444 was generally well tolerated. None of the subjects developed any serious clinical or laboratory AEs or discontinued the study due to an AE. All AEs were mild or moderate, and no dose-related trends were observed. Forty-six AEs were reported in 18 subjects (30.0%). AEs considered to be related to the study drug were headache (6 cases), dizziness (2), nausea (1), epistaxis (1), and increased heart rate (1). All AEs resolved spontaneously. CONCLUSIONS: A single dose of LC15-0444 exhibited linear PK properties over the range of 50 to 400 mg in these healthy Korean male subjects. PK characteristics were not significantly influenced by food. In addition, doses >or=200 mg of LC15-0444 inhibited plasma DPP IV activity by >80% over a 24-hour dosing interval, and a 600-mg dose increased active glucagon-like peptide-1 levels after a standardized meal. LC15-0444 was generally well tolerated.

Gemigliptin, a novel dipeptidyl peptidase (DPP)-4 inhibitor, is approved for use as a monotherapy or in combination therapy to treat hyperglycemia in patients with type 2 diabetes mellitus. In this study, we investigated the pharmacological profiles of gemigliptin in vitro and in vivo and compared them to those of the other DPP-4 inhibitors. Gemigliptin was a reversible and competitive inhibitor with a Ki value of 7.25+/-0.67nM. Similar potency was shown in plasma from humans, rats, dogs, and monkeys. The kinetics of DPP-4 inhibition by gemigliptin was characterized by a fast association and a slow dissociation rate compared to sitagliptin (fast on and fast off rate) or vildagliptin (slow on and slow off rate). In addition, gemigliptin showed at least >23,000-fold selectivity for DPP-4 over various proteases and peptidases, including DPP-8, DPP-9, and fibroblast activation protein (FAP)-alpha. In the rat, dog, and monkey, gemigliptin showed more potent DPP-4 inhibitory activity in vivo compared with sitagliptin. In mice and dogs, gemigliptin prevented the degradation of active glucagon-like peptide-1 by DPP-4 inhibition, which improved glucose tolerance by increasing insulin secretion and reducing glucagon secretion during an oral glucose tolerance test. The long-term anti-hyperglycemic effect of gemigliptin was evaluated in diet-induced obese mice and high-fat diet/streptozotocin-induced diabetic mice. Gemigliptin dose-dependently decreased hemoglobin A1c (HbA1c) levels and ameliorated beta-cell damage. In conclusion, gemigliptin is a potent, long-acting, and highly selective DPP-4 inhibitor and can be a safe and effective drug for the long-term treatment of type 2 diabetes.

Retinal pericyte loss and neovascularization are characteristic features of diabetic retinopathy. Gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has shown robust blood-glucose lowering effects in type 2 diabetic patients, but its effects on diabetic retinopathy have not yet been reported. We evaluated the efficacy of gemigliptin on retinal vascular leakage in db/db mice, which is an animal model for type 2 diabetes, and neovascularization in oxygen-induced retinopathy (OIR) mice, which is an animal model for ischemic proliferative retinopathy. Gemigliptin (100mg/kg/day) was orally administered to the db/db mice for 12weeks. C57BL/6 mice on postnatal day 7 (P7) were exposed to 75% hyperoxia for 5days, followed by exposure to room air from P12 to P17 to induce OIR. Gemigliptin (50mg/kg/day) was intraperitoneally injected daily from P12 to P17. Retinal neovascularization was analyzed in flat-mounted retinas on P17. We determined the efficacy and possible mechanism of gemigliptin on high glucose-induced apoptosis of primary human retinal pericytes. The oral administration of gemigliptin for 4months significantly ameliorated retinal pericyte apoptosis and vascular leakage in the db/db mice. Gemigliptin also ameliorated retinal neovascularization in the OIR mice. Gemigliptin attenuated the overexpression of plasminogen activator inhibitor-1 (PAI-1) in the retinas of diabetic and OIR mice. Gemigliptin and PAI-1 siRNA significantly inhibited pericyte apoptosis by inhibiting the overexpression of PAI-1, which is induced by high glucose. Our results suggest that gemigliptin has potent anti-angiogenic and anti-apoptotic activities via suppressing DPP-4 and PAI-1, and the results support the direct retinoprotective action of gemigliptin.

The direct effects of dipeptidyl peptidase-IV (DPP-IV) inhibitors on endoplasmic reticulum (ER) stress-induced apoptosis and inflammation in cardiomyocytes have not been elucidated. H9c2 cell viability, which was reduced by tunicamycin, was increased after DPP-IV inhibitor gemigliptin treatment. Gemigliptin significantly decreased the tunicamycin-mediated increase in glucose regulated protein 78 (GRP78) expression and ER stress-mediated signaling molecules such as protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C-EBP homologous protein (CHOP) and inositol-requiring enzyme 1alpha (IRE1alpha)/c-Jun N-terminal kinase (JNK)-p38. Furthermore, gemigliptin effectively induced Akt phosphorylation in a dose-dependent manner. Using flow cytometry and Hoechst staining, we showed that treatment with Akt inhibitor significantly blocked the anti-apoptotic effects mediated by gemigliptin. The reduction in tunicamycin-induced GRP78 level and PERK/CHOP pathway activity by gemigliptin was reversed after treatment with Akt inhibitor. In conclusion, gemigliptin effectively inhibited ER stress-induced apoptosis and inflammation in cardiomyocytes via Akt/PERK/CHOP and IRE1alpha/JNK-p38 pathways, suggesting its direct protective role in cardiovascular diseases.

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.

BACKGROUND: LC15-0444 is a selective inhibitor of dipeptidyl peptidase (DPP) IV under investigation in Korea for the treatment of type 2 diabetes. OBJECTIVE: The aim of this study was to investigate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of a single dose of LC15-0444 in healthy male subjects. METHODS: A dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study was performed in healthy Korean male subjects assigned to receive 25, 50, 100, 200, 400, or 600 mg of LC15-0444 capsules. Blood and urine samples were collected up to 72 hours after administration. Plasma and urine drug concentrations were determined by tandem mass spectrometry coupled with high-performance liquid chromatography. DPP IV activity was measured by continuous spectrophotometric assay. An additional food effect study was performed in the 100-mg dose group; changes in PK and PD parameters after high-fat diet were evaluated. Adverse events (AEs) were detected through investigator inquiries, spontaneous reports, and clinical evaluations such as physical examinations, vital sign measurements, 12-lead electrocardiography, clinical laboratory tests (eg, hematology, blood chemistry, coagulation, urinalysis), and computerized impedance cardiography. RESULTS: Sixty Korean men (mean age, 25.3 years [range, 19-39 years]; weight, 68.3 kg [range, 53.6-84.9 kg]) were enrolled, providing 10 subjects for each dose group. After administration, LC15-0444 reached T(max) at 0.5 to 5.1 hours, and was eliminated with a t((1/2)) of 16.7 to 21.3 hours. The mean fraction of unchanged drug excreted in urine ranged from 0.21 to 0.34 and mean renal clearance was 15.5 to 23.6 L/h. The dose-normalized AUC exhibited dose-linearity over the range of 50 to 400 mg. All doses of LC15-0444 =200 mg were found to inhibit 80% of DPP IV activity for 24 hours. High-fat diet did not significantly influence the AUC of LC15-0444. LC15-0444 was generally well tolerated. None of the subjects developed any serious clinical or laboratory AEs or discontinued the study due to an AE. All AEs were mild or moderate, and no dose-related trends were observed. Forty-six AEs were reported in 18 subjects (30.0%). AEs considered to be related to the study drug were headache (6 cases), dizziness (2), nausea (1), epistaxis (1), and increased heart rate (1). All AEs resolved spontaneously. CONCLUSIONS: A single dose of LC15-0444 exhibited linear PK properties over the range of 50 to 400 mg in these healthy Korean male subjects. PK characteristics were not significantly influenced by food. In addition, doses >or=200 mg of LC15-0444 inhibited plasma DPP IV activity by >80% over a 24-hour dosing interval, and a 600-mg dose increased active glucagon-like peptide-1 levels after a standardized meal. LC15-0444 was generally well tolerated.