Siglivia Mechanism of Action

Pharmacology: Pharmacodynamics: Sitagliptin act as highly selective dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, resulting in increased and prolonged active incretin levels. Incretin hormones (e.g., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) are part of an endogenous system involved in regulation of homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. Inhibition of DPP-4 results in reduced fasting and postprandial blood glucose concentrations in patients with type 2 diabetes mellitus.
Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 with no effect on DPP-8 or DPP-9 in vitro at concentrations approximating those from therapeutic dosage. Co-administration of Sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin action are glucose dependent, did not lower blood glucose or cause hypoglycemia with healthy subject.
Pharmacokinetics: Absorption: The absolute bioavailability of Sitagliptin is approximately 87%. The drug is rapidly absorbed following oral administration, with a peak plasma concentration occurring about 1 to 4 hours after an oral dose. Following the administration of 50 mg or 100 mg of Sitagliptin, approximately 80% inhibition of DPP-4 activity persists for 12 or 24 hours, respectively. Food does not appear to affect absorption. Administration of Sitagliptin with a high-fat meal had no effect on the pharmacokinetics of the drug.
Distribution: The volume of distribution is 198 L. Sitagliptin is 38% reversible bound to plasma proteins.
Metabolism: Sitagliptin undergoes minimal metabolism, mainly by the cytochrome P450 isoenzyme CYP3A4, and to a lesser extent by CYP2C8. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3) and P-glycoprotein.
Excretion: Sitagliptin is eliminated principally by kidneys via active tubular secretion. The drug is excreted in urine 87% (mainly as unchanged drug) and in feces 13%. The terminal half-life is about 12.4 hours. The renal clearance is about 350 mL/min.
Renal impairment: Plasma AUC of Sitagliptin was increased by approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (eGFR ≥60 mL/min/1.73 m² to <90 mL/min/1.73 m²) and patients with moderate renal impairment (eGFR ≥45 mL/min/1.73 m² to <60 mL/min/1.73 m²), respectively. Because increases of magnitude are not clinically relevant, dosage adjustment in these patients is not necessary.
In patients with moderate (eGFR ≥30 mL/min/1.73 m² to <45 mL/min/1.73 m²) to severe (eGFR <30 mL/min/1.73 m², including patients with ESRD on hemodialysis) renal impairment, Sitagliptin plasma AUC increased 2- and 4-fold, respectively. Lower dosages are recommended in patient with eGFR <45 mL/min/1.73 m². See Dosage & Administration.
Type 2 Diabetes: The pharmacokinetics of Sitagliptin in patients with type 2 diabetes are generally similar to those in healthy subjects.
Body mass index, sex and race: Body mass index, sex and race do not have clinically meaningful effect on Sitagliptin pharmacokinetics.
Hepatic impairment: Sitagliptin AUC and C_max increased approximately 21% and 13%, respectively, in subjects with moderate hepatic impairment (Child-Pugh class B). No dosage adjustment is necessary for patients with mild or moderate hepatic impairment. Severe hepatic impairment is not expected to affect the pharmacokinetics of Sitagliptin.
Pediatric: The Pharmacokinetics of Sitagliptin (single dose of 50 mg, 100 mg or 200 mg) were investigated in pediatric patients (10 to 17 years of age) with type 2 diabetes. In this population, the dose-adjusted AUC of Sitagliptin in plasma was approximately 18% lower compared to adult to patients with type 2 diabetes for a 100 mg dose. This is not considered to be a clinically meaningful difference based on the flat PK/PD relationship between the dose of 50 mg and 100 mg in adults.
No studies with Sitagliptin have been performed in pediatric patients <10 years old.
Elderly: Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of Sitagliptin compared to younger subjects. No dosage adjustment is required based on age.