Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: A double-blind, randomized, placebo-controlled study in healthy male volunteers

• Published in: Clinical therapeutics Vol. 28; no. 1; pp. 55 - 72
• Main Authors: Bergman, Arthur J., Stevens, Catherine, Zhou, YanYan, Yi, Bingming, Laethem, Martine, De Smet, Marina, Snyder, Karen, Hilliard, Deborah, Tanaka, Wesley, Zeng, Wei, Tanen, Michael, Wang, Amy Q., Chen, Li, Winchell, Gregory, Davies, Michael J., Ramael, Steven, Wagner, John A., Herman, Gary A.
• Format: Journal Article
• Language: English
• Published: Belle Mead, NJ EM Inc USA 2006; Excerpta Medica; Elsevier Limited
• Subjects: Administration, Oral; Adolescent; Adult; antihyperglycemic agents; Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes. Impaired glucose tolerance; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - drug effects; dipeptidyl peptidase-IVinhibitor; Dose-Response Relationship, Drug; Double-Blind Method; DPP-IV; Drug dosages; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Follow-Up Studies; Glucagon; Glucagon-Like Peptide 1 - blood; Glucose; Humans; incretins; Insulin-Like Growth Factor Binding Protein 3 - blood; Insulin-Like Growth Factor I - metabolism; Male; Medical sciences; Metabolism; Metabolites; Middle Aged; MK-0431; Pharmacokinetics; Pharmacology. Drug treatments; Polypeptides; Pyrazines - administration & dosage; Pyrazines - pharmacokinetics; Reference Values; sitagliptin; Sitagliptin Phosphate; Triazoles - administration & dosage; Triazoles - pharmacokinetics; type 2 diabetes; incretins; sitagliptin; type 2 diabetes; DPP-IV; antihyperglycemic agents; MK-0431; dipeptidyl peptidase-IVinhibitor; Endocrinopathy; Type 2 diabetes; Dipeptidyl-peptidase IV; Human; dipeptidyl peptidase- IV inhibitor; Healthy subject; Enzyme; Oral administration; Metabolic diseases; Biological activity; Multiple dose; Peptidases; Hypoglycemic agent; Randomization; Placebo; Double blind study; Hydrolases; Inhibitor; Pharmacokinetics
• DOI: 10.1016/j.clinthera.2006.01.015
• ISSN: 0149-2918

Dipeptidyl peptidase-IV (DPP-IV) inhibitorsrepresent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin. This double-blind, randomized, placebo-controlled,incremental oral-dose study was conducted at SGS Biopharma, Antwerp, Belgium. Healthy, nonsmoking male volunteers aged 18 to 45 years with a creatinine clearance rate of >80 mL/min and normoglycemia and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 8 treatment groups: sitagliptin 25, 50, 100, 200, or 400 mg or placebo, QD for 10 days; a single dose of sitagliptin 800 mg administered on day 1 followed by 600 mg QD on days 3 to 10; or sitagliptin 300 mg BID for 10 days. For analysis of PK properties, plasma and urine samples were obtained before study drug administration on day 1 and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 16 hours after study drug administration on day 1; before study drug administration on days 2 to 9; and every 24 hours for 96 hours after the last dose on day 10, and analyzed for sitagliptin concentrations. Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis. Seventy subjects were enrolled (mean age, 32.9 years [range, 18–45 years]; mean weight, 79.7 kg [range, 63.4–97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T max, C max, and t ½) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05–1.29), and the apparent terminal elimination t ½ was 11.8 to 14.4 hours. At steady state in the sitagliptin QD groups, the mean proportion of drug excreted unchanged in the urine was ∼70.6%. Dose-dependent inhibition of plasma DPP-IV activity was apparent, and the pattern of inhibition at steady state (day 10) was statistically similar to that observed on day 1. Day-10 weighted mean inhibition of plasma DPP-IV activity over 24 hours was ≥ 80% for doses of ≥ 50 mg QD. After a standard meal, active GLP-1 concentrations were significantly increased in the sitagliptin groups by ∼2-fold compared with that in the control group, a finding consistent with near-maximal acute glucose lowering in preclinical studies. Across doses, no apparent adverse effects, including hypoglycemia, were found or reported. The results from this study in a select population of healthy male volunteers suggest that multiple oral doses of sitagliptin inhibited plasma DPP-IV activity and affected active GLP-1 concentrations in a dose-dependent manner, without producing hypoglycemia. Multiple dosing of sitagliptin exhibited a PK/PD profile consistent with that of a QD regimen and was well tolerated.