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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.
Clin Pharmacol Ther. 2005 Dec; 78(6):675-88.CP

Abstract

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.

Authors+Show Affiliations

Merck & Co., Whitehouse Station, NJ 07065, USA. gary_herman@merck.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

16338283

Citation

Herman, Gary A., et al. "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." Clinical Pharmacology and Therapeutics, vol. 78, no. 6, 2005, pp. 675-88.
Herman GA, Stevens C, Van Dyck K, et al. 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. Clin Pharmacol Ther. 2005;78(6):675-88.
Herman, G. A., Stevens, C., Van Dyck, K., Bergman, A., Yi, B., De Smet, M., Snyder, K., Hilliard, D., Tanen, M., Tanaka, W., Wang, A. Q., Zeng, W., Musson, D., Winchell, G., Davies, M. J., Ramael, S., Gottesdiener, K. M., & Wagner, J. A. (2005). 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. Clinical Pharmacology and Therapeutics, 78(6), 675-88.
Herman GA, et al. 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. Clin Pharmacol Ther. 2005;78(6):675-88. PubMed PMID: 16338283.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Herman,Gary A, AU - Stevens,Cathy, AU - Van Dyck,Kristien, AU - Bergman,Arthur, AU - Yi,Bingming, AU - De Smet,Marina, AU - Snyder,Karen, AU - Hilliard,Deborah, AU - Tanen,Michael, AU - Tanaka,Wesley, AU - Wang,Amy Q, AU - Zeng,Wei, AU - Musson,Donald, AU - Winchell,Gregory, AU - Davies,Michael J, AU - Ramael,Steven, AU - Gottesdiener,Keith M, AU - Wagner,John A, PY - 2005/05/04/received PY - 2005/09/01/accepted PY - 2005/12/13/pubmed PY - 2006/4/28/medline PY - 2005/12/13/entrez SP - 675 EP - 88 JF - Clinical pharmacology and therapeutics JO - Clin Pharmacol Ther VL - 78 IS - 6 N2 - 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. SN - 0009-9236 UR - https://www.unboundmedicine.com/medline/citation/16338283/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_ L2 - https://doi.org/10.1016/j.clpt.2005.09.002 DB - PRIME DP - Unbound Medicine ER -