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

  • Herman G
  • Stevens C
  • Van Dyck K
 et al. 
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Background: 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. Methods: 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. Results: 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. Conclusions: 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. Copyright © 2005 by the American Society for Clinical Pharmacology and Therapeutics.

Author-supplied keywords

  • 4 oxo 4 [3 (trifluoromethyl) 5,6 dihydro[1,2,4]tri
  • Administration, Oral
  • Adolescent
  • Adult
  • Analysis of Variance
  • Antigens, CD26
  • Area Under Curve
  • Blood Glucose
  • C-Peptide
  • Common Cold
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Enzyme Inhibitors
  • Eye Diseases
  • Fasting
  • Glucagon-Like Peptide 1
  • Half-Life
  • Headache
  • Humans
  • Insulin
  • Male
  • Middle Aged
  • Pyrazines
  • Triazoles
  • adult
  • article
  • clinical trial
  • common cold
  • controlled clinical trial
  • controlled study
  • dipeptidyl peptidase IV inhibitor
  • drug absorption
  • drug tolerability
  • eye irritation
  • glucose blood level
  • half life time
  • headache
  • human
  • male
  • normal human
  • priority journal
  • randomized controlled trial
  • sitagliptin
  • unclassified drug

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  • G A Herman

  • C Stevens

  • K Van Dyck

  • A Bergman

  • B Yi

  • M De Smet

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