Fortesia Mechanism of Action

Therapeutic Class: Fortesia is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. The DPP-4 inhibitors are a class of agents that act as incretin enhancers. By inhibiting the DPP-4 enzyme, sitagliptin increases the levels of two known active incretin hormones, 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. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. This mechanism is unlike the mechanism seen with sulfonylureas; sulfonylureas cause insulin release even when glucose levels are low, which can lead to sulfonylurea-induced hypoglycaemia in patients with type 2 diabetes and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogues, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-glucosidase inhibitors, and amylin analogues.
Pharmacology: Mechanism of Action: Fortesia is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors, which improve glycaemic control in patients with type 2 diabetes by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon like peptide-1 (GLP1) and glucose dependent insulinotropic polypeptide (GIP) are released by the intestine throughout the day and levels are increased in response to a meal, 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 signalling pathways involving cyclic AMP. Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyses the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4 thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretins levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower haemoglobin A_1c (HbA_1c) and lower fasting and postprandial glucose concentrations. The glucose dependent mechanism of sitagliptin is distinct from the mechanism of sulfonylureas, which increase secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely related enzymes DPP-8 or DPP-9 at therapeutic concentrations.
Pharmacodynamics: General: In patients with type 2 diabetes, administration of single oral doses of Fortesia Tablet leads to inhibition of DPP-4 enzyme activity for a 24-hour period, resulting in a 2-to-3-fold increase in circulating levels of active GLP-1 and GIP, increased plasma levels of insulin and C-peptide, decreased glucagon concentrations, reduced fasting glucose and reduced glucose excursion following an oral glucose load or a meal.
Sitagliptin alone increased only active GLP-1 concentrations, reflecting inhibition of DPP-4, whereas metformin alone increased active and total GLP-1 concentrations to a similar extent.
Pharmacokinetics: Absorption: The absolute bioavailability of sitagliptin is approximately 87%. Since co-administration of a high fat meal with Fortesia Tablet had no effect on the pharmacokinetics, Fortesia may be administered with or without food.
Distribution: The mean volume of distribution of steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma 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.
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.
Elimination: Following administration of an oral [¹⁴C] sitagliptin dose, approximately 100% of the administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week of dosing. The apparent terminal t_1/2 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. 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 which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce clearance of sitagliptin.
Renal impairment: Sitagliptin was modestly removed by haemodialysis (13.5% over a 3- to 4-hour haemodialysis session starting 4 hours post dose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring haemodialysis.
Hepatic impairment: No dosage adjustment for Fortesia Tablet is necessary for patients with mild or moderate hepatic insufficiency. There is no clinically 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 pharmacokinetic of sitagliptin.
Elderly: No dosage adjustment is required based on age. Elderly subjects (65 to 85 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Paediatric: No studies with sitagliptin have been performed in paediatric patients <10 years of age.
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 pharmacokinetic of sitagliptin in patients with type 2 diabetes are generally similar to those in healthy subjects.