Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses

• Published in: Clinical pharmacology and therapeutics Vol. 78; no. 6; p. 675
• Main Authors: Herman, Gary A, Stevens, Cathy, Van Dyck, Kristien, Bergman, Arthur, Yi, Bingming, De Smet, Marina, Snyder, Karen, Hilliard, Deborah, Tanen, Michael, Tanaka, Wesley, Wang, Amy Q, Zeng, Wei, Musson, Donald, Winchell, Gregory, Davies, Michael J, Ramael, Steven, Gottesdiener, Keith M, Wagner, John A
• Format: Journal Article
• Language: English
• Published: United States 01.12.2005
• Subjects: Administration, Oral; Adolescent; Adult; Analysis of Variance; Area Under Curve; Blood Glucose - analysis; C-Peptide - blood; Common Cold - chemically induced; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - metabolism; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Eye Diseases - chemically induced; Fasting - blood; Glucagon-Like Peptide 1 - blood; Half-Life; Headache - chemically induced; Humans; Insulin - blood; Male; Middle Aged; Pyrazines - administration & dosage; Pyrazines - blood; Pyrazines - pharmacokinetics; Sitagliptin Phosphate; Triazoles - administration & dosage; Triazoles - blood; Triazoles - pharmacokinetics
• ISSN: 0009-9236
• DOI: 10.1016/j.clpt.2005.09.002

Sitagliptin (MK-0431 [(2R)-4-oxo-4-(3-[trifluoromethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7[8H]-yl)-1-(2,4,5-trifluorophenyl)butan-2-amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-IV) currently in phase III development for the treatment of type 2 diabetes. Two double-blind, randomized, placebo-controlled, alternating-panel studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of sitagliptin (1.5-600 mg) in healthy male volunteers. Sitagliptin was well absorbed (approximately 80% excreted unchanged in the urine) with an apparent terminal half-life ranging from 8 to 14 hours. Renal clearance of sitagliptin averaged 388 mL/min and was largely uninfluenced by the dose administered. The area under the plasma concentration-time curve for sitagliptin increased in an approximately dose-dependent manner and was not meaningfully influenced by food. Single doses of sitagliptin markedly and dose-dependently inhibited plasma DPP-IV activity, with approximately 80% or greater inhibition of DPP-IV activity occurring at 50 mg or greater over a 12-hour period and at 100 mg or greater over a 24-hour period. Compared with placebo, sitagliptin produced an approximately 2-fold increase in postmeal active glucagon-like peptide 1 levels. Sitagliptin was well tolerated and was not associated with hypoglycemia. This study provides proof of pharmacologic characteristics for sitagliptin in humans. By inhibiting plasma DPP-IV activity, sitagliptin increases the postprandial rise in active glucagon-like peptide 1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. Sitagliptin possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen.