Trevia Mechanism of Action

Anti-Diabetic [Dipeptidyl Peptidase 4 (DPP-4) Inhibitor].
Pharmacology: Pharmacodynamics: Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.
Pharmacokinetics: Absorption: Following oral administration of a 100 mg dose, sitagliptin absorbs rapidly with peak plasma concentration (median T_max) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin is 8.52 μm·hr, with C_max 950 nM. The absolute bioavailability of sitagliptin is approximately 87%. Plasma AUC of sitagliptin increased in a dose-proportional manner and increased approximately 14% following 100 mg doses at steady-state compared to the first dose.
Distribution: The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metabolism: Sitagliptin is primarily eliminated unchanged in urine (approximately 79%), and metabolism is a minor pathway. Following a [¹⁴C] sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Excretion: Following administration of an oral [¹⁴C] sitagliptin dose, approximately 100% of the administered radioactivity eliminate in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t_1/2 following a 100 mg oral dose of sitagliptin is approximately 12.4 hours and renal clearance is approximately 350 mL/min. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of P-glycoprotein (P-gp), which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a P-gp inhibitor, did not reduce the renal clearance of sitagliptin.
Special Populations: Renal Insufficiency: Patients with mild renal insufficiency did not have a clinically meaningful increase in the plasma concentration of sitagliptin. The plasma AUC of sitagliptin increases approximately 2-fold in patients with moderate renal insufficiency, and an approximately 4-fold in patients with severe renal insufficiency and in patients with ESRD on hemodialysis. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3 to 4 hour hemodialysis session starting 4 hours post dose). To achieve plasma concentration of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with eGFR <45 mL/min/1.73 m².
Hepatic Insufficiency: There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9). However, because sitagliptin is primarily renally eliminated, severe hepatic insufficiency is not expected to affect the pharmacokinetics of sitagliptin.
Elderly: Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Type 2 diabetes: The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.