Gliptadin Mechanism of Action

Pharmacodynamics: The Dipeptidyl Peptidase 4 inhibitors are class of agents that act as incretin enhancers. Sitagliptin increases the levels of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), when the DPP-4 enzyme is inhibited. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. As the blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production.
General: In a study of patients with type 2 diabetes, administration of single oral dose of sitagliptin resulted to a significant reduction of glucose levels. This is the same case with those patients with type 2 diabetes who are in an inadequately controlled metformin monotherapy. In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia, suggesting that the insulinotropic and glucagon suppressive actions of the drug are glucose dependent.
Effects on blood pressure: Based on studies in hypertensive patients on one or more anti-hypertensive drugs (including angiotensin-converting enzyme inhibitors, angiotensin-II antagonists, calcium-channel blockers, beta-blockers and diuretics), co-administration of sitagliptin was generally well tolerated. Reductions in the blood pressure of subjects with normal blood pressure have not been observed.
Cardiac Electrophysiology: Healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase of the placebo-corrected mean change in QTc from baseline at 3 hours post dose was 8.0 msec. This small increase was not considered to be clinically significant. Patients with type 2 diabetes taking 100 mg or 200 mg dose of sitagliptin did not have meaningful change in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
Pharmacokinetics: Sitagliptin was rapidly absorbed with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose after oral administration of 100 mg dose to healthy subjects. The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Absorption: Sitagliptin has an absolute bioavailability of approximately 87% and may be administered with or without food.
Distribution: The fraction of sitagliptin reversibly bound to plasma protein is low (38%).
Metabolism: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.
Elimination: Approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing following the administration of an oral [¹⁴C] sitagliptin dose to healthy subjects. The apparent terminal t_½ following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
Characteristics in Patients: Renal Impairment: Compared to normal healthy control subjects, there is an approximately 1.2 fold and 1.6 fold increase in plasma AUC of sitagliptin in patients with mild renal impairment (eGFR ≥60 mL/min/1.73 m² to <90 mL/min/1.73 m²) and in moderate renal impairment (eGFR ≥45 mL/min/1.73 m² to <60 mL/min/1.73 m²). Increases of this magnitude are not clinically relevant and dosage adjustment in these patients is not necessary.
An approximately 2-fold increase in plasma AUC of sitagliptin in patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m² to <45 mL/min/1.73 m²) and approximately 4-fold increase approximately in plasma AUC of sitagliptin in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) including patients with ESRD on hemodialysis were observed.
Lower dosages are recommended in patients with eGFR <45 mL/min/1.73 m² to achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function.
Hepatic Impairment: No dosage adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9). However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly: No dosage adjustment is required based on age. Age has no clinically meaningful impact on the pharmacokinetics of sitagliptin.
Pediatrics: No studies with sitagliptin have been performed in pediatric patients.
Gender: No dosage adjustment is necessary based on gender.
Race: No dosage adjustment is necessary based on race.
Body Mass Index (BMI): No dosage adjustment is necessary based on BMI.
Type 2 Diabetes: The pharmacokinetics of sitagliptin in patients with type 2 diabetes are generally similar to those in healthy subjects.