Single-dose escalation study of yogliptin in healthy Chinese volunteers.

Abstract

BACKGROUND\nYogliptin is a novel xanthine dipeptidyl peptidase-4 (DPP-4) inhibitor targeting type 2 diabetes. After promising preclinical pharmacological studies, the first human trial of yogliptin was designed.\n\n\nMETHODS\nA randomized, double-blind, parallel, placebo-controlled phase I single-dose escalation study was designed to evaluate the pharmacokinetics, pharmacodynamics, and tolerability after single oral doses of yogliptin in healthy Chinese subjects. Healthy subjects were assigned to nine cohorts, which received a single dose of yogliptin at 2.5, 5, 10, 25, 50, 100, 200, 400, or 600\u202fmg. Two subjects in each cohort received placebo. Blood samples were collected before dosing and up to 192\u202fh afterwards. Urine samples were collected until 120\u202fh after dosing. Plasma and urine drug concentrations were determined using liquid chromatography coupled with tandem mass spectrometry, and DPP-4 activity was measured using a semi-quantitative, fluorescence-based kinetic assay.\n\n\nRESULTS\nA total of 104 subjects were enrolled, 103 of whom completed the study (mean age, 25.3\u202fyears; mean weight, 58.8\u202fkg; mean BMI, 21.8\u202fkg/m2). A total of 27 adverse events (AEs) occurred in 25 of 86 yogliptin subjects (29.1%), and 3 AEs occurred in 3 of 18 placebo subjects (16.7%). Yogliptin was absorbed with a median time of maximum observed concentration (Tmax) of 3.0\u202fh and was eliminated slowly with a t1/2 of 25.45-43.84\u202fh. The maximum observed concentration (Cmax) and area under the curve (AUC) varied slightly more than dose-proportionally over the dose range from 2.5 to 400\u202fmg. The fraction of drug excreted in urine ranged from 8.39% to 24.77%. Mean DPP-4 inhibition at 24\u202fh after dosing ranged from 97.7% to 99.5%, and DPP-4 inhibition was >80% for 72\u202fh at doses from 25 to 400\u202fmg. DPP-4 inhibition was >80% for 1\u202fweek in the group receiving 400\u202fmg.\n\n\nCONCLUSION\nYogliptin was well tolerated in healthy subjects, with no dose-limiting toxicity observed in the range from 2.5 to 600\u202fmg. Yogliptin inhibited plasma DPP-4 activity for 72\u202fh at single doses of 25-200\u202fmg and for 1\u202fweek at 400\u202fmg, suggesting that once-weekly dosing of yogliptin is possible in type 2 diabetes patients.\n\n\nTRIAL REGISTRATION\nChiCTR-IIR-17010311 (Chictr.org).