Multiple-dose pharmacokinetics and pharmacodynamics of evogliptin (DA-1229), a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers

Abstract

PurposeEvogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase IV (DPP-IV) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles and tolerability of evogliptin after repeated oral administration in healthy subjects.Patients and methodsA block-randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed in a total of 30 subjects. Repeated once-daily doses of 5, 10, or 20 mg evogliptin or the same doses of placebo were orally administered to ten subjects in each dosage group for 10 days. Subjects in each group were randomized to receive evogliptin or placebo with a ratio of 8:2. Pharmacokinetics of evogliptin were evaluated, with its concentrations in serial plasma and urine samples collected following the first and last administrations. DPP-IV activity and glucagon-like peptide-1, glucose, and insulin levels were quantified to evaluate evogliptin’s pharmacodynamics on the first and last dosing days.ResultsAll participants completed the study without any serious or severe adverse event. The evogliptin plasma concentration reached its peak within 4–5 hours and decreased relatively slowly, with a terminal elimination half-life of 33–39 hours. Repeated administration resulted in a 1.4- to 1.5-fold accumulation. Evogliptin’s systemic exposure and inhibition of plasma DPP-IV activity increased in a dose-dependent manner. Inhibition of DPP-IV activity >80% was sustained over 24 hours in all evogliptin dose groups and provided an increase in postprandial active glucagon-like peptide-1 levels by 1.5- to 2.4-fold. Postprandial glucose levels in the evogliptin-treated groups were reduced 20%–35% compared to placebo, but were not accompanied by increased insulin levels.ConclusionRepeated administration of evogliptin in healthy subjects was well tolerated and exhibited linear pharmacokinetics within the 5–20 mg dose range. A once-daily regimen of 5–20 mg evogliptin effectively inhibited DPP-IV activity.

Effects of renal impairment on the pharmacokinetics and pharmacodynamics of a novel dipeptidyl peptidase‐4 inhibitor, evogliptin (DA‐1229)

“…The PK and PD characteristics of evogliptin were assessed after a single dose in the RI group without diabetes, although these characteristics of linagliptin were previously evaluated under steady‐state conditions . Evogliptin had linear PK characteristics; thus, its PK and PD characteristics could be assessed via a single‐dose study . Although people with T2DM differ from those without diabetes, we assumed that similar results would be obtained for the two patient groups, as DPP‐4 activity has been shown to be an effective surrogate biomarker for the glucose regulatory effects of DPP‐4 inhibitors …”

“…Additionally, the efficacy and safety of evogliptin have been shown to be similar to those of sitagliptin in patients with T2DM not adequately controlled by metformin monotherapy. Evogliptin has linear pharmacokinetic (PK) characteristics, and its main route of elimination in humans is the non‐renal route, in association with the human cytochrome P450 3A (CYP3A) enzyme . The fraction excreted unchanged in the urine of evogliptin is 17% to 34% of the administered dose, and the renal clearance (CL R ) rate is ~30% total apparent clearance (CL/F) in humans …”

“…Evogliptin has linear pharmacokinetic (PK) characteristics, and its main route of elimination in humans is the non-renal route, in association with the human cytochrome P450 3A (CYP3A) enzyme. 4,5 The fraction excreted unchanged in the urine of evogliptin is 17% to 34% of the administered dose, and the renal clearance (CL R ) rate is~30% total apparent clearance (CL/F) in humans. 4,5 Renal impairment (RI), one of the complications of T2DM, can alter the PK and pharmacodynamic (PD) characteristics of DPP-4 inhibitors, leading to requirements for dose adjustments of some agents.…”

Efficacy and safety of adding evogliptin versus sitagliptin for metformin‐treated patients with type 2 diabetes: A 24‐week randomized, controlled trial with open label extension

“…Evogliptin is a novel antidiabetic agent that potently and selectively inhibits DPP‐4. Namyi Gu et al reported the pharmacokinetic and pharmacodynamic profiles of evogliptin in healthy subjects . The peak plasma concentration of evogliptin was reached within 4 to 5 hours.…”

“…The inhibition of DPP‐4 activity (>80%) was sustained for over 24 hours, and it provided an increase in postprandial active GLP‐1 levels, 1.5‐ to 2.4‐fold. As a result, evogliptin reduced postprandial glucose by 20% to 35% compared to placebo . And another study reported the pharmacokinetic and pharmacodynamic profiles of evogliptin in renal impairment; the plasma concentration of evogliptin increased 1.98 times in severe renal impairment, but within a therapeutic window .…”