シタグリプチン

Pharmaceuticals -> Alimentary tract and metabolism -> Drugs used in diabetes

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Breast Feeding; Lactation; Milk, Human; Hypoglycemic Agents; Incretins; Dipeptidyl-Peptidase IV Inhibitors; DPP-4 Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

MW: 523.32. White to off-white crystalline, non-hygroscopic powder. Soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; insoluble in isopropanol and isopropyl acetate. /Sitagliptin phosphate monohydrate/

This chemical does not meet GHS hazard criteria for 2.4% (1 of 41) of reports.

Danger

H302 (92.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P260, P264, P264+P265, P270, P280, P301+P317, P305+P354+P338, P317, P319, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 41 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl sitagliptin phosphate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sitagliptin phosphate/

Suitable extinguishing agents: water spray, carbon dioxide, dry chemical powder or foam. Protective equipment: wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes. /Sitagliptin phosphate monohydrate/

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves Measures for cleaning/collecting absorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, fedreal, state and local regulations/. /Sitagliptin phosphate monohydrate/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Handling should only be performed by personnel trained and familiar with handling of potent active pharmaceutical ingredients. /Sitagliptin phosphate monohydrate/

Information for safe handling: avoid inhalation and contact with skin, eyes and clothing ... . /Sitagliptin phosphate monohydrate/

Concomitant administration of cyclosporine and sitagliptin may increase absorption and plasma concentrations of sitagliptin. However, this interaction is not considered clinically important.

Sitagliptin and metformin have a potential additive effect on active glucagon-like peptide (GLP-1) concentrations. Pharmacokinetic interactions are unlikely. The relevance of these effects to glycemic control in patients with type 2 diabetes mellitus is unclear.

There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or Januvia is recommended.

When sitagliptin was used in combination with a sulfonylurea or insulin, the incidence of hypoglycemia was greater than that in patients receiving placebo with a sulfonylurea or insulin. In a long-term (52-week) clinical noninferiority study, rates of hypoglycemia with sitagliptin/metformin combination therapy were lower than those observed with glipizide/metformin combination therapy. However, in a 24-week clinical study, rates of hypoglycemia in patients receiving sitagliptin and glimepiride with or without metformin were greater than those in patients receiving glimepiride and metformin. Patients receiving sitagliptin may require a lower dosage of a concomitant insulin secretagogue (e.g., sulfonylurea) or insulin to reduce the risk of hypoglycemia.

Liver injury due to sitagliptin is rare. In large clinical trials, serum enzyme elevations were no more common with sitagliptin therapy (0.5%) than with placebo (0.4%), and no instances of clinically apparent liver injury were reported. Since licensure, instances of serum enzyme elevations attributed to sitagliptin have been reported to the FDA and the sponsor. A single case report of clinically apparent liver injury has been published, but in a patient who also had hepatitis C. The pattern of serum enzyme elevations was hepatocellular and peak serum bilirubin was 9.4 mg/dL, with a rapid recovery upon stopping sitagliptin. Immunoallergic features and autoantibodies were absent.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3.4X10+4(SRC), determined from a structure estimation method(2), indicates that sitagliptin is expected to be immobile in soil(SRC). The estimated pKa of sitagliptin is 8.78(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of sitagliptin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.6X10-15 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Sitagliptin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.9x10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2014).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3.4X10+4(SRC), determined from a structure estimation method(2), indicates that sitagliptin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.6X10-15 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 4(SRC), from an estimated log Kow of 1.39(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2014).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), sitagliptin, which has an estimated vapor pressure of 2.9X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase sitagliptin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4 hours(SRC), calculated from its rate constant of 1.0X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase sitagliptin may be removed from the air by wet and dry deposition(SRC). Sitagliptin contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Sitagliptin is a viscous liquid. It is a dipeptidyl peptidase-4 inhibitor and used to improve glycemic control in patients with type 2 diabetes. HUMAN EXPOSURE AND TOXICITY: Sitagliptin improves glycemic control and is generally well-tolerated in patients with type 2 diabetes. Sitagliptin use has been associated with an increased risk of heart failure -related hospitalizations among patients with type 2 diabetes with pre-existing heart failure. More recently a study has pointed to the possible use of sitagliptin in the treatment of some neurodegenerative conditions of the peripheral nervous system. Sitagliptin appears to be free from the adverse effects of weight gain and hypoglycemia that are associated some other treatments. ANIMAL STUDIES: Renal and liver toxicity were observed in rodents at systemic exposure to sitagliptin at values 58 times the human exposure level. Transient treatment-related physical signs, some of which suggest neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical exposure level. Carcinogenicity studies in mice did not show an increased incidence of tumors in any organ up to 500 mg/kg, but in rats there was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. Reproductive effects in rats and rabbits were only seen at doses greater than 250 mg/kg. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO cells, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of sitagliptin can be estimated to be 3.43X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that sitagliptin is expected to be immobile in soil. The estimated pKa of sitagliptin is 8.78(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ /The purpose of the study was/ to evaluate the effect of sitagliptin on somatosensory-evoked potentials (SEPs) and metabolic control in patients with type 2 diabetes mellitus without clinical diabetic neuropathy. ... Patients with less than six months from the diagnosis were included. Examinations of SEPs and laboratory tests at fasting and after food stimulation were performed before and after three months of treatment with sitagliptin (100 mg/day). There was a reduction in the mean levels of HbA1c (P < 0.0001), fasting glucose (P = 0.001), total cholesterol (P = 0.019), and ALT (P = 0.022). An increase in active GLP-1 was found at the end of the study (P = 0.0025). Several SEPs showed statistically significant differences when analyzed before and after treatment with sitagliptin. The results give a glimpse of the possible use of sitagliptin in the treatment of some neurodegenerative conditions of the peripheral nervous system, in addition to its already established role in glycemic control.

/SIGNS AND SYMPTOMS/ Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been reported during postmarketing experience in patients receiving sitagliptin or sitagliptin/metformin. The most common manifestations associated with pancreatitis were abdominal pain, nausea, and vomiting. Hospitalization was required in 66% of 88 reported cases, including 2 cases of hemorrhagic or necrotizing pancreatitis that necessitated prolonged hospitalization and intensive-care unit (ICU) care. Pancreatitis occurred within 30 days of initiation of sitagliptin or sitagliptin/metformin therapy in 21% of cases; discontinuance of the drug led to resolution of pancreatitis in 53% of patients. At least one other risk factor (e.g., obesity, high cholesterol and/or triglyceride concentrations) was noted in 51% of cases.

/SIGNS AND SYMPTOMS/ There have been postmarketing reports of serious allergic and hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative skin conditions such as Stevens-Johnson syndrome); rash, urticaria, and cutaneous vasculitis also have been reported. The onset of such reactions usually was within the first 3 months following treatment initiation, but such reactions may occur after the first dose.

/SIGNS AND SYMPTOMS/ Worsening of renal function, including acute renal failure that sometimes required dialysis, has been reported in some patients during postmarketing experience. A subset of these patients had renal insufficiency, some of whom were prescribed inappropriate dosages of sitagliptin.

For more Human Toxicity Excerpts (Complete) data for SITAGLIPTIN (16 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

sitagliptin

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 4 was calculated in fish for sitagliptin(SRC), using an estimated log Kow of 1.39(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for sitagliptin is estimated as 2.6X10-15 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that sitagliptin is expected to be essentially nonvolatile from water and moist soil surfaces(2). Sitagliptin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.9X10-8 mm Hg(SRC), determined from a fragment constant method(3).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl sitagliptin phosphate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sitagliptin phosphate/

A10BH01

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

Inhibition of DPP-4 by sitagliptin slows DPP-4 mediated inactivation of incretins like GLP-1 and GIP. Incretins are released throughout the day and upregulated in response to meals as part of glucose homeostasis. Reduced inhibition of incretins increase insulin synthesis and decrease glucagon release in a manner dependant on glucose concentrations. These effects lead to an overall increase in blood glucose control which is demonstrated by reduced glycosylated hemoglobin (HbA1c).

Januvia is a member of a class of oral anti-hyperglycemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement in glycemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) 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 signaling 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 hypoglycemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes 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 incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycemia, these changes in insulin and glucagon levels lead to lower hemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulfonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycemia 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 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. Concentrations of the active intact hormones are increased by Januvia, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. 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, Januvia increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

Approximately 12.4 hours. Other studies have reported a half life of approximately 11 hours.

Two double-blind, randomized, placebo-controlled, alternating-panel studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of sitagliptin (1.5-600 mg) in healthy male volunteers. Sitagliptin was well absorbed (approximately 80% excreted unchanged in the urine) with an apparent terminal half-life ranging from 8 to 14 hours. ...

The apparent terminal half life following a 100 mg oral dose of sitagliptin was approximately 12.4 hours ... .

Sitagliptin is mostly not metabolised, with 79% of the dose excreted in the urine as the unchanged parent compound. Minor metabolic pathways are mediated mainly by cytochrome p450(CYP)3A4 and to a lesser extent by CYP2C8. After 18 hours, 81% of the dose has remained unchanged, while 2% has been N-sulfated to the M1 metabolite, 6% has been oxidatively desaturated and cyclized to the M2 metabolite, <1% glucuronidated at an unknown site to the M3 metabolite, <1% has been carbamoylated and glucuronidated to the M4 metabolite, 6% has been oxidatively saturated and cyclized to the M5 metabolite, and 2% has been hydroxylated at an unknown site to the M6 metabolite. The M2 metabolite is the cis isomer while the M5 metabolite is the trans isomer of the same metabolite.

The metabolism and excretion of (14)C sitagliptin ... were investigated in humans after a single oral dose of 83 mg/193 muCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.

Following a (14)C 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.

QFP0P1DV7Z

SITAGLIPTIN

Established Pharmacologic Class [EPC] - Dipeptidyl Peptidase 4 Inhibitor

Mechanisms of Action [MoA] - Dipeptidyl Peptidase 4 Inhibitors

Sitagliptin is a Dipeptidyl Peptidase 4 Inhibitor. The mechanism of action of sitagliptin is as a Dipeptidyl Peptidase 4 Inhibitor.

SITAGLIPTIN

Substances which lower blood glucose levels.

Peptides which stimulate INSULIN release from the PANCREATIC BETA CELLS following oral nutrient ingestion, or postprandially.

Compounds that suppress the degradation of INCRETINS by blocking the action of DIPEPTIDYL-PEPTIDASE IV. This helps to correct the defective INSULIN and GLUCAGON secretion characteristic of TYPE 2 DIABETES MELLITUS by stimulating insulin secretion and suppressing glucagon release.

Sitagliptin is 87% orally bioavailable and taking it with or without food does not affect its pharmacokinetics. Sitagliptin reaches maximum plasma concentration in 2 hours.

Approximately 79% of sitagliptin is excreted in the urine as the unchanged parent compound. 87% of the dose is eliminated in the urine and 13% in the feces.

198L.

350mL/min.

Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk.

Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

MEDICATION

Hypoglycemic Agents

Use (kg; approx.) in Germany (2009): >5000

Table: Sitagliptin Phosphate Preparations [Table#7210]

Table: Sitagliptin Phosphate Combinations Preparations [Table#7211]

Xelevia /Sitagliptin monophosphate monohydrate/

Tesavel /Sitagliptin monophosphate monohydrate/