Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects

Background: Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. Objective: This study was conducted to characterize the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of alogliptin in healthy male subjects. Methods: This was a randomized, double-blind, placebo-controlled study in which healthy, nonobese male subjects between the ages of 18 and 55 years were assigned to I of 6 cohorts: alogliptin 25, 50, 100, 200, 400, or 800 mg. One subject in each cohort received placebo. An ascending-dose strategy was used, in which each cohort received its assigned dose only after review of the safety data from the previous cohort. Blood and urine were collected over 72 hours after dosing for pharmacokinetic analysis and determination of plasma DPP-4 inhibition and active glucagon-like peptide-1 (GLP-1) concentrations. Results: Thirty-six subjects (6 per cohort) were enrolled and completed the study (29/36 [81%] white; mean age, 26.6 years; mean weight, 76.0 kg). Alogliptin was rapidly absorbed (median T-max,1-2 hours) and eliminated slowly (mean t(1/2), 12.4-21.4 hours), primarily via urinary excretion (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60%-71%). Cm, increased dose x and AUC(0-infinity) proportionally over the range from 25 to 100 mg. The metabolites M-I (N-demethylated) and M-II (N-acetylated) accounted for < 2% and < 6%, respectively, of alogliptin concentrations in plasma and urine. Across alogliptin doses, mean peak DPP-4 inhibition ranged from 93% to 99%, and mean inhibition at 24 hours after dosing ranged from 74% to 97%. Exposure to active GLP-1 was 2- to 4-fold greater for all alogliptin doses compared with placebo; no dose response was apparent. Hypoglycemia (asymptomatic) was reported in 5 subjects (1 receiving alogliptin 50 mg, 2 receiving alogliptin 200 mg, I receiving alogliptin 400 mg, 1 receiving placebo). Other adverse events were reported in I subject each: dizziness; (alogliptin 100 mg), syncope (alogliptin 200 mg), constipation (alogliptin 200 mg), viral infection (alogliptin 400 mg), hot flush (placebo), and nausea (placebo). Conclusion: In these healthy male subjects, alogliptin at single doses up to 800 mg inhibited plasma DPP-4 activity, increased active GLP-1, and was generally well tolerated, with no dose-limiting toxicity.