Safety, Pharmacokinetics, and Pharmacodynamics of a Dipeptidyl Peptidase‐4 Inhibitor: A Randomized, Double‐Blinded, Placebo‐Controlled Daily Administration of Fotagliptin Benzoate for 14 Days for Type 2 Diabetes Mellitus

Abstract

This study investigated the pharmacokinetics, pharmacodynamics, and safety of fotagliptin benzoate (fotagliptin), a dipeptidyl peptidase-4 (DPP-4) inhibitor, in Chinese patients with type 2 diabetes mellitus (T2DM). In a randomized, doubleblinded, placebo-controlled study, 10 and 4 patients with T2DM were randomized and received, respectively, once-daily oral fotagliptin (24 mg) or placebo, for 14 days. The pharmacokinetics and pharmacodynamics were assessed throughout the study, including monitoring DPP-4, glucagon-like peptide-1 (GLP-1), glycosylated hemoglobin, and fasting blood glucose. Fotagliptin was rapidly absorbed, and the median time to maximum concentration value was ∼1.5 hours. Plasma fotagliptin levels were stable after 14 days of once-daily dosage. The accumulation ratios for the area under the plasma concentration-time curve of fotagliptin, M1, and M2-1, were 1.19 ± 0.10, 1.59 ± 0.27, and 1.39 ± 0.26, respectively. The durations for DPP-4 inhibition >80% in the fotagliptin group on days 1 and 14 were 23.5 and 24.0 hours, respectively. The concentrations of GLP-1 were higher on days 1 and 14 than at the baseline. No serious complications occurred. Fotagliptin showed favorable pharmacokinetics and pharmacodynamics and was well tolerated. Treatment with fotagliptin can achieve high DPP-4 inhibition and increase plasma GLP-1. A once-per-day dosing regimen may be recommended as clinically efficacious.

Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial

“…These may be attributed to the pharmacokinetic and pharmacodynamic results of both fotagliptin and alogliptin. One recent study in Chinese patients with T2DM indicated that fotagliptin could increase plasma GLP-1 concentration while DPP-4 inhibition was continuously maintained at a steady state [ 12 ]. Still, relevant results were based on the design of the study and patients were closely monitored to ensure that they followed the diet and exercise guidelines of the trail.…”

“…Fotagliptin was not primary metabolized by cytochrome P450 enzymes. There were 2 major metabolites, M1 had no inhibitory effect on DPP-4, M2-1 had slight inhibition [ 12 ]. The efficacy and safety profiles of fotagliptin have been characterized in previous studies.…”

“…Fotagliptin exhibited favorable pharmacokinetic results as it can achieve high and steady DPP-4 inhibition. Fotagliptin was rapidly absorbed, which t max was obtained at 1–2 h in T2DM patients, also enabling a maximum inhibition of DPP-4 within 1–2 h post administration [ 12 , 13 ]. Recently, a phase 1 clinical trial has been conducted in fourteen eligible Chinese patients with T2DM, which showed that fotagliptin was safe and well tolerated [ 12 ].…”

“…Fotagliptin was rapidly absorbed, which t max was obtained at 1–2 h in T2DM patients, also enabling a maximum inhibition of DPP-4 within 1–2 h post administration [ 12 , 13 ]. Recently, a phase 1 clinical trial has been conducted in fourteen eligible Chinese patients with T2DM, which showed that fotagliptin was safe and well tolerated [ 12 ]. In a phase 2 clinical study, patients who were treated with fotagliptin monotherapy of 6 mg, 12 mg and 24 mg once a day for 12 weeks showed significant improvement in the HbA1c control as compared with placebo.…”

Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants

“…Shu et al from XuanZhu Pharma identified compound 65 (imigliptin, DPP-4 IC 50 = 9.0 nM) via a scaffold-hopping approach from alogliptin, which is a highly selective and oral active DPP-4 inhibitor entering into phase II clinical trials . Fosun Pharma reported a 5-oxo-1,2,4-triazine derivative 66 (fotagliptin, DPP-4 IC 50 = 2.2 nM) in phase III clinical trials in China. , Xie et al reported a pyrrolopyrimidine analogue 67 as a potent DPP-4 inhibitor (DPP-4 IC 50 = 1.4 nM) with greater in vivo efficacy than alogliptin . Wu et al from Merck designed the tricyclic heterocycle 68 as a potent DPP-4 inhibitor (DPP-4 IC 50 = 1.7 nM) that demonstrated robust glucose-lowering efficacy after oral administration in mice and potential for a long duration of action .…”