알로글리프틴(ALOGLIPTINE,ALOGLIPTINA)

When alogliptin is used in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy. Therefore, patients receiving alogliptin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Liver injury due to alogliptin is rare. In large clinical trials, serum enzyme elevations were uncommon (1% to 3%) and no greater than with comparator arms or placebo. In these studies, no instances of clinically apparent liver injury with jaundice were reported. Since licensure, instances of serum enzyme elevations and acute hepatitis including acute liver failure attributed to alogliptin have been reported to the FDA and the sponsor. These cases have not been reported in the literature and the clinical features have not been defined. Cases of clinically apparent acute liver injury have been reported with other DPP-4 inhibitors such as sitagliptin and saxagliptin. The latency to onset was typically within 2 to 12 weeks of starting and the pattern of liver enzyme elevations was usually hepatocellular. Immunoallergic features were often present. Most cases were self-limited in course and rapidly reversed once the medication was stopped.；Likelihood score: E* (unproven but suspected cause of acute, idiosyncratic liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 940(SRC), determined from a structure estimation method(2), indicates that alogliptin is expected to have low mobility in soil(SRC). The estimated pKa of alogliptin is 9.47(3), indicating that this compound will exist almost entirely 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 alogliptin from moist soil surfaces is not expected to be an important fate process because alogliptin exists as a cation and cations do not volatilize(SRC). Alogliptin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.1X10-12 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 940(SRC), determined from a structure estimation method(2), indicates that alogliptin is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.47(3) indicates alogliptin will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water or moist soil surfaces and bioconcentration are not expected to be important fate processes. 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), alogliptin, which has an estimated vapor pressure of 3.1X10-12 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase alogliptin may be removed from the air by wet and dry deposition(SRC). Alogliptin contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

According to the drug manufacturer's package insert, severe hypersensitivity reactions, including anaphylaxis, have been reported with alogliptin. Other severe adverse reactions include:；* Stevens-Johnson syndrome；* Hepatic failure；* Heart failure (associated with alogliptin and saxagliptin; per FDA drug safety communication bulletin)；* Tubulointerstitial nephritis；* Pancreatitis；* Severe or disabling arthralgia (a class effect of DPP-4 inhibitor; per FDA drug safety communication bulletin; see below for additional details)；* Hypoglycemia; typically mild；* Bullous pemphigoid (see below for additional details)；* Rhabdomyolysis；More common adverse reactions include nasopharyngitis, which occurred in 4.4% of patients, as well as headache and upper respiratory tract infections, which were reported in 4.2% of patients. Renal function abnormalities were more frequently observed in patients with high cardiovascular risk, occurring in 23% of those with cardiovascular risk compared to 3% in those without cardiovascular risk.；A concern related to adverse events is arthralgia. In 2015, the FDA issued a warning that DPP-4 inhibitors, including alogliptin, may be associated with serious arthralgias. A meta-analysis published in 2017, which evaluated 67 randomized controlled trials, suggested a significantly increased risk of overall arthralgia (P=.003), but a nonsignificant increase in serious arthralgias (P=.20). When prescribing DPP-4 inhibitors, including alogliptin, clinicians should weigh the benefits of glycemic control against the potential risk of arthralgia.；Bullous pemphigoid, a cutaneous autoimmune blistering disorder, has been reported as an adverse effect of DPP-4 inhibitors. In most cases, symptoms resolve after discontinuation of the drug and treatment with topical or immunosuppressive therapy. Patients who develop blisters should discontinue the DPP-4 inhibitor and consult a dermatologist for further evaluation and management.；Baseline liver function tests are recommended due to reports of fatal and nonfatal hepatic failure in postmarketing surveillance. Evaluating for underlying liver disease may be warranted.；Cases of pancreatitis have been reported, and alogliptin should be discontinued immediately if pancreatitis is suspected.；Alogliptin is not associated with weight gain, unlike some other oral glycemic control medications.；Drug-Drug Interactions；* Alogliptin is contraindicated for use with other DPP-4 inhibitors (such as linagliptin, saxagliptin, and sitagliptin).；* Insulin and insulin secretagogues, including sulfonylureas, increase the risk of hypoglycemia. Reducing the insulin dosage may be necessary to minimize this risk when used with alogliptin tablets.

IDENTIFICATION AND USE: Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; but not for treatment of type 1 diabetes or diabetic ketoacidosis. HUMAN EXPOSURE AND TOXICITY: During clinical trials patients receiving alogliptin 25 mg daily reported adverse reactions including pancreatitis (0.2%), hypersensitivity reactions (0.6%), a single event of serum sickness, nasopharyngitis (4.4%), hypoglycemia (1.5%), headache (4.2%) and upper respiratory tract infection (4.2%). In elderly patients the incidence of hypoglycemia with alogliptin increased to 5.4%. Postmarketing, patients taking alogliptin reported acute pancreatitis and serious hypersensitivity reactions. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking Nesina. ANIMAL STUDIES: In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating or fertility at doses up to 500 mg/kg, or approximately 172 times the clinical dose based on plasma drug exposure (AUC). Alogliptin administered to pregnant rabbits and rats during the period of organogenesis was not teratogenic at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, respectively, the clinical dose based on plasma drug exposure (AUC). Doses of alogliptin up to 250 mg/kg (approximately 95 times clinical exposure based on AUC) given to pregnant rats from gestation Day 6 to lactation Day 20 did not harm the developing embryo or adversely affect growth and development of offspring. Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats. Alogliptin is secreted in the milk of lactating rats in a 2:1 ratio to plasma. No drug-related tumors were observed in mice after administration of 50,

Signs and Symptoms of Overdose；In clinical trials, healthy participants were given doses of up to 800 mg, whereas participants with T2D received doses of 400 mg. No severe adverse effects were observed at these high doses.；Management of Overdose；In the event of an overdose, clinical monitoring and supportive therapy should be provided. Alogliptin is minimally dialyzable, with only 7% removed during a 3-hour hemodialysis session, making hemodialysis unlikely to be effective. A medical toxicologist or the Poison Control Center should be contacted (at 1-800-222-1222) for current recommendations.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of alogliptin can be estimated to be 940(SRC). According to a classification scheme(2), this estimated Koc value suggests that alogliptin is expected to have low mobility in soil. The estimated pKa of alogliptin is 9.47(3), indicating that this compound will exist almost entirely 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/ Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects ... a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs /was performed/. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1alpha (SDF-1alpha) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1alpha, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1alpha-cAMP pathway activation.

/HUMAN EXPOSURE STUDIES/ In a randomized, placebo-controlled, four-arm, parallel-group study, 257 subjects were administered either alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg or placebo once daily for a total of seven days. No increase in QTc was observed with either dose of alogliptin. At the 400 mg dose, peak alogliptin plasma concentrations were 19-fold higher than the peak concentrations following the maximum recommended clinical dose of 25 mg.

/HUMAN EXPOSURE STUDIES/ The highest doses of Nesina administered in clinical trials were single doses of 800 mg to healthy subjects and doses of 400 mg once daily for 14 days to patients with type 2 diabetes (equivalent to 32 times and 16 times the maximum recommended clinical dose of 25 mg, respectively). No serious adverse events were observed at these doses. ...

/SIGNS AND SYMPTOMS/ There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking Nesina, although some of the reports contain insufficient information necessary to establish the probable cause.

For more Human Toxicity Excerpts (Complete) data for Alogliptin (11 total), please visit the HSDB record page.

An estimated pKa of 9.47(1) indicates alogliptin will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. Alogliptin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.1X10-12 mm Hg(SRC), determined from a fragment constant method(2).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Rats were administered oral doses of 75, 400 and 800 mg/kg alogliptin for two years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on AUC exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150 or 300 mg/kg alogliptin for two years, or up to approximately 51 times the maximum recommended clinical dose of 25 mg, based on AUC exposure.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The toxicity potential of alogliptin was evaluated in a series of repeated dose toxicity studies in rats and dogs of up to 26 and 39 weeks in duration, respectively. In rats, the main target organs of toxicity of alogliptin were the liver, kidney and urinary bladder. Moderate liver toxicity was noted at doses of > or = 900 mg/kg/day as reflected by elevated serum AST, ALT and/or ALP activities, increased liver weights, as well as minimal to mild centrilobular hepatocellular hypertrophy. At doses of > or = 1333 mg/kg/day, in addition to the liver, toxicities on kidney and urinary bladder were evident. In the kidneys, renal tubular degeneration and/or regeneration and renal tubular dilatation and/or necrosis were observed. In the urinary bladder, transitional cell hyperplasia (simple or papillary/nodular), hemorrhage, and inflammation, erosion/ulceration, and dilatation were noted. The urinary bladder and/or kidney complications contributed in part to an increase in mortality in rats from 1333 to 2000 mg/kg/day. The no-observed-adverse-effect-level in rats was 400 mg/kg, approximately 147 times the exposure in humans at the maximum recommended human adult dose (MRHD) of 25 mg alogliptin. In dogs, reddened ears and facial swelling, without associated histopathological changes, were noted at doses of > or = 30 mg/kg/day. The no-observed-adverse-effect-level in dogs derived from the 39-week study was 100 mg/kg/day, approximately 112 times the exposure in humans at the MRHD.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Doses of alogliptin up to 250 mg/kg (approximately 95 times clinical exposure based on AUC) given to pregnant rats from gestation Day 6 to lactation Day 20 did not harm the developing embryo or adversely affect growth and development of offspring. Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Alogliptin administered to pregnant rabbits and rats during the period of organogenesis was not teratogenic at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, respectively, the clinical dose based on plasma drug exposure (AUC). Doses of alogliptin up to 250 mg/kg (approximately 95 times clinical exposure based on AUC) given to pregnant rats from gestation Day 6 to lactation Day 20 did not harm the developing embryo or adversely affect growth and development of offspring. Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.

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

MEDICATION

Hypoglycemic Agents

Table: Alogliptin benzoate Preparations [Table#8191]

Table: Alogliptin benzoate Combinations Preparations [Table#8192]