Sitagliptin

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/

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/