Alogliptin

Alogliptin is an Antidiabetic Agent belonging to the pharmacologicalclass of Dipeptyl peptidase-4 (DPP-4) inhibitors.

Alogliptin is approved for treating type 2 diabetes mellitus. It is used to improve glycemic control by blocking the enzyme DPP-4. It helps control blood sugar levels by enhancing insulin release and reducing glucose production by the liver, thereby improving glycemic control in individuals with type 2 diabetes.

After oral treatment, alogliptin rapidly absorbs and has a bioavailability of around 100%. It metabolises very little in the liver and is mostly eliminated unchanged in the urine. Since the elimination half-life is approximately 12 hours, a once-daily dose can treat type 2 diabetes.

Alogliptin's most common side effects include hypoglycemia, nasopharyngitis, upper respiratory tract infection, headache, abdominal pain, gastroesophageal reflux disease, diarrhoea, itching, and rash.

Alogliptin is available in the form of Oral Tablets.

The molecule is available in the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.

Alogliptin is an Antidiabetic Agent belonging to the pharmacological class of Dipeptyl peptidase-4 (DPP-4) inhibitors.

In response to meals, the small intestine releases higher levels of the incretin hormones into the circulation, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The dipeptidyl peptidase-4 (DPP-4) enzyme quickly inactivates these hormones, which release insulin from the pancreatic beta cells in a glucose-dependent manner. Additionally, GLP-1 decreases pancreatic alpha cell release of glucagon, which lessens hepatic glucose synthesis. Although GLP-1 concentrations are lower in type 2 diabetic individuals, the insulin response to GLP-1 is still there. Alogliptin, a DPP-4 inhibitor, increases the blood levels of incretin hormones and delays their inactivation, which reduces fasting and postprandial glucose levels in a glucose-dependent way in people with type 2 diabetes mellitus. When used in amounts that approximate therapeutic exposures, the drug alogliptin specifically binds to and inhibits DPP-4 activity, although not the activity of DPP-8 or DPP-9.

Alogliptin is available in the form of Oral Tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

Treatment of Type 2 diabetes mellitus

Alogliptin can be used to treat Diabetes mellitus, type 2, treatment. By improving the release of insulin and reducing the quantity of glucose generated by the liver, it helps with blood sugar regulation. Usually, alogliptin is used along with a healthy diet and regular exercise.

In Treatment of Type 2 diabetes mellitus

Alogliptin helps boost the amount of insulin your body generates following a meal and prevents excessive glucose (sugar) release into the blood. In doing so, it decreases your body's blood glucose levels. It often only causes a single frequent adverse effect and is taken once each day.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

Orally: Alogliptin is available as a tablet that can be taken orally. Alogliptin should be taken on an empty stomach or with food. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 6.25mg, 12.5mg, 25mg

Alogliptin is available in the form of Oral Tablets.

Dose Adjustment in Adult Patients:

Diabetes Mellitus Type 2: 25 mg PO qDay

Dosing Considerations

It is not recommended for use in managing type 1 diabetes mellitus or diabetic ketoacidosis since it would not be efficient in these conditions.

Assess renal function before starting alogliptin and then on periodically after that.

Alogliptin should be used in treating Diabetes Mellitus, along with appropriate nutritional limits.

While taking Alogliptin, maintain regular meal schedules with balanced macronutrient content to help stabilize blood sugar levels.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation.

Avoid consuming sugary foods and beverages, including cereals, snacks, and sweetened beverages, as they can lead to rapid spikes in blood glucose.

It is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Alogliptin may be contraindicated in the following conditions:-

• Hypersensitivity reaction to alogliptin or any of its excipients, including anaphylaxis, angioedema, or
• Severe cutaneous adverse reactions, including Stevens-Johnson syndrome

• Pancreatitis: It is unclear if consuming alogliptin tablets increases the risk of pancreatitis in individuals with a history of the condition. Patients should be monitored for pancreatitis symptoms and signs after taking alogliptin tablets. Alogliptin pills should be immediately stopped, and proper care is necessary if pancreatitis is suspected.
• Heart Failure: In the EXAMINE study that involved patients with type 2 diabetes with recent acute coronary syndrome, 106 (3.9%) of those receiving alogliptin tablets and 89 (3.3%) of those receiving placebo pills required hospitalization for congestive heart failure. Before starting treatment in patients at risk for heart failure, such as those with a history of renal impairment or heart failure, weigh the risks and benefits of alogliptin tablets. Also, watch for these patients' heart failure symptoms as they go through treatment. Patients should be informed of the signs and symptoms specific to heart failure and instructed to report them immediately. Consider stopping the use of alogliptin tablets and managing the situation per current standards of care if heart failure develops.

• Hypersensitivity Reactions: In individuals using alogliptin tablets, there have been postmarketing reports of severe hypersensitivity reactions. Severe cutaneous adverse effects, such as Stevens-Johnson syndrome, angioedema, and anaphylaxis, are among these responses. Stop taking the alogliptin pills, look into other possible reasons, and start a different diabetic regimen if a significant hypersensitivity response is detected. It is uncertain if individuals who have previously had angioedema after taking a dipeptidyl peptidase-4 (DPP-4) inhibitor would be more susceptible to experiencing it again after taking alogliptin tablets. These individuals should be treated with caution
• Hepatic Effects: Reports of fatal and nonfatal hepatic failure; type 2 DM is also known to produce fatty liver disease and increase liver enzyme levels. If LFTs are increased, keep a close eye on things and stop taking alogliptin immediately. If the liver test results are abnormal, do not resume taking the medication. If liver damage is identified and no other possible cause, do not continue treatment.
• Bullous Pemphigoid: The use of DPP-4 inhibitors has been associated with postmarketing cases of bullous pemphigoid that required hospitalization; patients typically recovered with topical or systemic immunosuppressive therapy and the discontinuation of DPP-4 inhibitor; advise patients to report the emergence of blisters or erosions while undergoing therapy; Therapy should be stopped, and referred to a dermatologist for diagnosis, and appropriate treatment should be undertaken if bullous pemphigoid is suspected.
• A lower insulin dose or an insulin secretagogue may be required to reduce the risk of hypoglycemia because it is known that both insulin and insulin secretagogues, such as sulfonylureas, can cause hypoglycemia.

It is unsafe to consume Alogliptin with alcohol.

There is no sufficient scientific evidence traceable regarding the use and safety of Alogliptin in breastfeeding.

It is generally considered safe to use Alogliptin during pregnancy.

Limit Alcohol consumption, Minimize or avoid sugary drinks or high-carb foods like soda and fruit juices.

The adverse reactions related to Alogliptin can be categorized as

• Hypoglycemia; is higher when added to insulin
• Nasopharyngitis, headache or Upper respiratory tract infection
• Hypersensitivity or Pancreatitis

Reports on Postmarketing

Severe arthralgia that is debilitating

Angioedema, rash, urticaria, and anaphylaxis

Stevens-Johnson syndrome and other severe cutaneous adverse effects

Increases in hepatic enzymes

Fatal hepatic failure

Pemphigoid bullous

Rhabdomyolysis

Constipation

Diarrhoea

Nausea

Ileus

Renal tubulointerstitial nephritis

The clinically relevant drug interactions of Alogliptin are briefly summarized here.

• CYP3A4 Inhibitors: Medications that inhibit CYP3A4 enzymes, such as certain antifungal drugs, may increase alogliptin levels, potentially leading to an increased risk of side effects.

• CYP3A4 Inducers: Drugs that induce CYP3A4 enzymes, like certain anticonvulsants and rifampin, may decrease alogliptin levels in the body, potentially reducing its effectiveness.

• Insulin or Sulfonylureas: When alogliptin is combined with insulin or sulfonylureas, there's an increased risk of hypoglycemia (low blood sugar). Dose adjustments may be needed.
• Diuretics (water pills): Diuretics like thiazides can affect blood sugar levels. Monitoring and adjusting the diabetes treatment may be necessary.

The most common side effects of Alogliptin includes-

• Combining hypoglycemia (low blood sugar) with insulin or sulphonylurea
• Nasopharyngitis (inflammation of the nasal passages and throat)
• An upper respiratory infection
• Pain in the stomach
• Gastroesophageal reflux disease
• Diarrhoea
• Rash
• Itching

• Pregnancy

Pregnancy Category B: Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.

There is insufficient information on alogliptin's potential to cause severe birth abnormalities or miscarriages in pregnant women. Uncontrolled diabetes during pregnancy poses risks to both the mother and the foetus.

Based on plasma drug exposure (AUC), alogliptin was administered to pregnant rats and rabbits during organogenesis at 180 and 149 times the 25 mg therapeutic dosage, respectively, with no adverse developmental effects detected.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnancy-related diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm birth, and delivery difficulties are all increased risks for mothers when their diabetes is uncontrolled. Significant birth abnormalities, stillbirths, and morbidity associated with macrosomia are more likely in a foetus with poorly managed diabetes.

Animal Data

According to plasma drug exposure (AUC), administering alogliptin to pregnant rabbits and rats during the organogenesis phase did not negatively impact their ability to grow. These dosages were 200 mg/kg and 500 mg/kg, or 149 and 180 times, respectively, the 25 mg therapeutic dose. Following oral treatment to pregnant rats, placental transfer of alogliptin into the foetus was seen.

Alogliptin was given to pregnant rats throughout gestation and lactation at dosages as high as 250 mg/kg (about 95 times the 25 mg therapeutic dose, based on AUC), with no harmful developmental effects seen in the offspring.

• Nursing Mothers

There is no information on alogliptin's presence in human milk, its effects on nursing infants, or its impact on milk production. Rat milk contains alogliptin; however, because lactation physiology varies between species, quantities in human milk may not be accurately predicted using information from animal lactation. Along with the mother's clinical requirement for alogliptin tablets, any potential adverse effects on the breastfed newborn from alogliptin tablets or the underlying maternal disease and the developmental and health advantages of nursing should all be taken into consideration.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have not been established.

• Geriatric Use

In clinical safety and effectiveness trials using alogliptin tablets, a total of 9052 individuals were included, and of them, 2257 (24.9%) and 386 (4.3%) were above the age of 65. Patients 65 years of age and younger showed no general differences in safety or efficacy. Although this clinical experience has not found any variations in reactions between senior and younger patients, it cannot be ruled out that specific older people may be more sensitive.

Dose Adjustment in Kidney Impairment Patients:

Mild (CrCl 60mL/min): No adjustment in dosage is necessary.

Moderate (CrCl ≥30 to <60 mL/min): Reduce the dosage to 12.5 mg PO daily.

Severe (CrCl ≥15 to <30 mL/min) or ESRD (CrCl <15 mL/min) or hemodialysis-required cases: 6.25 mg PO qDay

May deliver without respect to when dialysis will occur.

Dialysis of the peritoneum: unknown

Dose Adjustment in Hepatic Impairment Patients:

Mild-to-moderate (Child-Pugh A and B): No adjustment in dosage is necessary.

Severe (Child-Pugh C): Unknown

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Alogliptin.

Overconsumption of Alogliptin could lead to symptoms such as hypoglycemia/ hyperglycemia, weakness, headaches and GI disturbances.

Management

There is no specific antidote or treatment for excessive intake of Alogliptin. However, immediate medical attention is essential. Alogliptin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Activated charcoal or gastric lavage may also be considered if the overdose is detected shortly after ingestion to reduce absorption.

If the overdose leads to low blood sugar (hypoglycemia), treatment may involve administering oral glucose or intravenous (IV) dextrose to raise blood sugar levels. Management typically involves supportive measures like intravenous fluids, electrolyte replacement, and symptomatic treatment such as antiemetic medications for nausea and vomiting.

The patient will continue to be monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

After a single dosage is administered to healthy participants, DPP-4 inhibition peaks 2-3 hours later. Between dosages of 12.5 mg and 800 mg, DPP-4's peak inhibition approached 93%. For dosages more than or equivalent to 25 mg, the DPP-4 inhibition remained over 80% after 24 hours. Compared to placebo over 8 hours following a typical meal, an alogliptin equivalently showed reductions in postprandial glucagon while boosting postprandial active GLP-1 levels. The QTc interval is not impacted by alogliptin.

Cardiac Electrophysiology

In a randomized, placebo-controlled, four-arm, parallel-group research, 257 participants received either alogliptin 50 mg, alogliptin 400 mg, a placebo, or a 400 mg dose of moxifloxacin once daily for a total of seven days. Both doses of alogliptin did not increase corrected QT (QTc). Peak levels of alogliptin plasma were 19-fold greater at the 400 mg dosage than at the 25 mg maximum clinically advised dose.

Pharmacokinetics:

Absorption

Tablets of alogliptin have about 100% absolute bioavailability. The total and peak exposure to alogliptin are unaffected when the medication is administered together with a high-fat meal. As a result, either a meal or no food may be consumed with alogliptin pills.

Bioavailability: ~100%

Peak plasma time: 1-2 hr

Distribution

The volume of distribution at the terminal phase was 417 L after a single 12.5 mg intravenous infusion of alogliptin in healthy people, indicating that the drug is well dispersed into tissues.

Protein-bound: 20%

Vd: 417 L

Metabolism

Alogliptin doesn't go through an extensive amount of metabolism. N-demethylated alogliptin (1% of parent molecule) and N-acetylated alogliptin (6% of parent compound) were two minor metabolites. The N-demethylated metabolite inhibits DPP-4 and is active. The N-acetylated metabolite has no functional effect. Cytochrome enzymes CYP2D6 and CYP3A4 are involved in the metabolism of alogliptin. However, this is only partially the case. The cytochrome enzymes in the liver metabolize 10–20% of the dosage.

Active metabolite: N-demethylated (less than 1% of parent compound)

Inactive metabolite: N-acetylated alogliptin (more than 6% of parent compound)

Minor substrate of CYP3A4 and CYP2D6

Excretion

The primary route of [14C] alogliptin-derived radioactivity elimination is renal excretion (76%), with 13% recovered in the faeces, resulting in a total recovery of 89% of the injected radioactive dosage. The systemic clearance of alogliptin was 14.0 L/hr, while the renal clearance of 9.6 L/hr indicated some active renal tubular secretion.

Half-life: 21 hr

Renal clearance: 9.6 L/hr

Total body clearance: 14 L/hr

Excretion: 76% urine; 13% feces

• Dineen, Laura et al. “Alogliptin (nesina) for adults with type-2 diabetes.” P & T : a peer-reviewed journal for formulary management vol. 39,3 (2014): 186-202.
• Kaku, Kohei et al. “Benefit-Risk Assessment of Alogliptin for the Treatment of Type 2 Diabetes Mellitus.” Drug safety vol. 42,11 (2019): 1311-1327. doi:10.1007/s40264-019-00857-8
• Ueki K, Tanizawa Y, Nakamura J J-BRAND Registry Group, et al Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in the patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry) BMJ Open Diabetes Research and Care 2021;9:e001787. doi: 10.1136/bmjdrc-2020-001787
• Mita, T., Katakami, N., Yoshii, H. et al. Long-term efficacy and safety of early alogliptin initiation in the subjects with type 2 diabetes: an extension of the SPEAD-A study. Sci Rep 13, 14649 (2023). https://doi.org/10.1038/s41598-023-41036-1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Alogliptin was given orally to rats for two years at 75, 400, and 800 mg/kg dosages. According to the area under the plasma concentration curve (AUC) exposure, no drug-related tumours were seen up to 75 mg/kg or around 32 times the maximum clinically advised dose of 25 mg. The combined incidence of thyroid C-cell adenomas and carcinomas rose in male but not in female rats at higher doses (about 308 times the highest clinically advised dose of 25 mg). After two years of treatment of 50, 150, or 300 mg/kg of alogliptin, or up to 51 times the highest clinically advised dose of 25 mg, no drug-related tumours in mice were observed based on AUC exposure.

In cytogenetic testing using mouse lymphoma cells and the Ames test using S. typhimurium and E. coli, alogliptin was not mutagenic or clastogenic. The in vivo mouse micronucleus research on alogliptin was negative.

Alogliptin did not adversely impact early embryonic development, mating, or fertility in a rat fertility trial at doses up to 500 mg per kg, or around 172 times the therapeutic dosage based on plasma drug exposure (AUC).

• https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000PharmR.pdf
• https://www.ncbi.nlm.nih.gov/books/NBK507809/
• https://dailymed.nlm.nih.gov/dailymed/drugInfo.
• https://www.ncbi.nlm.nih.gov/books/NBK548275/