Teneligliptin

Teneligliptin is an Antidiabetic Agent, Dipeptidyl Peptidase IV (DPP-IV) Inhibitor belonging to pharmacology class of Antidiabetic.

Teneligliptin is indicated in the treatment of Diabetes mellitus, type 2, treatment.

Teneligliptin is Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 87%. Time to peak plasma concentration: 1-4 hours and Volume of distribution: Approx 198 L. Plasma protein binding: 38%. And get Minimally metabolised primarily by CYP3A4, and to a lesser extent by CYP2C8 isoenzyme into inactive metabolites and get Excreted Mainly via urine (87%; approx 79% as unchanged drug, 16% as metabolites); faeces (13%). Terminal elimination half-life: Approx 12.4 hours.

The common side effects associated with Teneligliptin include Hypoglycaemia (particularly in combination with sulfonylureas or insulins); worsening renal function, including acute renal failure (may require dialysis); severe and disabling arthralgia, bullous pemphigoid.

Teneligliptin is available in the form of Tablets.

Inhibition of DPP-4 by Teneligliptin 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 increases insulin synthesis and decrease glucagon release in a manner dependent on glucose concentrations These effects lead to an overall increase in blood glucose control which is demonstrated by reduced glycosylated hemoglobin (HbA1c)

The Tmax of Teneligliptin 1-4 hours.

Teneligliptin is available in Tablets

Oral: Administer without regard to meals.

Teneligliptin can be used in the treatment of Diabetes mellitus, type 2, treatment.

Teneligliptin inhibits dipeptidyl peptidase-4 (DPP-4) enzyme resulting in prolonged active incretin levels. Incretin hormones (e.g, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. Decreased glucagon secretion results in decreased hepatic glucose production. Under normal physiologic circumstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal; incretin hormones are rapidly inactivated by the DPP-4 enzyme.

Teneligliptin is approved for use in the following clinical indications

Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, as monotherapy or combination therapy.

Diabetes mellitus, type 2, treatment:

Note: May be used as an adjunctive agent or alternative monotherapy for select patients, including those in whom initial therapy with lifestyle intervention and metformin failed, or who cannot take metformin, particularly in patients close to glycemic goals when avoidance of hypoglycemia and/or weight gain is desirable; use is not associated with improvement in cardiovascular or renal outcomes .

Oral: Oral: 20 mg once daily.

Tablets: 20 mg.

Tablet

• Dose Adjustment in Hepatic Patient:

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

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Individualized medical nutrition therapy (MNT) based on American Diabetes Association (ADA) recommendations is an integral part of therapy.

Teneligliptin may be contraindicated in the following conditions:

● Serious hypersensitivity (eg, anaphylaxis, angioedema) to Teneligliptin or any component of the formulation.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Disease-related concerns:

Bariatric surgery:

Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery

Glucagon-like peptide-1 exposure and therapeutic efficacy: Closely monitor for signs and symptoms of pancreatitis; gastric bypass and sleeve gastrectomy may increase endogenous secretion of glucagon-like peptide-1 . A single-dose, placebo-controlled study evaluated short-term therapy (4 weeks) with Teneligliptin in gastric bypass patients having persistent or recurrent type 2 diabetes and found it to be well tolerated and provided a small but significant reduction in postprandial blood glucose

Renal impairment: Use with caution in patients with moderate to severe renal dysfunction and end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis; dosing adjustment required.

There is no sufficient scientific evidence traceable regarding use and safety of Teneligliptin in concurrent use with alcohol.

It is not known if Teneligliptin is present in breast milk.

• Pregnancy Category B
• Reproduction studies have been performed in rats and rabbits. Doses of Teneligliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
• Teneligliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
• Teneligliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
• Placental transfer of Teneligliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of Teneligliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

Take with or without food.

The adverse reactions related to Teneligliptin can be categorized as

Common Adverse effects: Hypoglycemia (particularly in combination with sulfonylureas or insulins); worsening renal function, including acute renal failure (may require dialysis); severe and disabling arthralgia, bullous pemphigoid

Less Common Adverse effects: Gastrointestinal: Diarrhea, nausea

Rare Adverse effects: Acute pancreatitis including hemorrhagic or necrotizing pancreatitis, serious hypersensitivity reactions (e.g. anaphylaxis, angioedema, cutaneous vasculitis, exfoliative skin conditions including Stevens-Johnson syndrome).

The clinically relevant drug interactions of Teneligliptin is briefly summarized here

Increased risk of hypoglycemia when co-administered with sulfonylureas (e.g. glipizide, glimepiride) and insulins; consider lowering the dose of insulins or sulfonylureas. May slightly increase the serum concentration of digoxin.

The common side of Teneligliptin include the following

Hypoglycemia (particularly in combination with sulfonylureas or insulins); worsening renal function, including acute renal failure (may require dialysis); severe and disabling arthralgia, bullous pemphigoid.

• Pregnancy Category B
• Reproduction studies have been performed in rats and rabbits. Doses of Teneligliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed
• Teneligliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
• Teneligliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
• Placental transfer of Teneligliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of Teneligliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
• Labor and Delivery

There is no FDA guidance on use of Teneligliptin during labor and delivery.

• Nursing Mothers

Teneligliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether Teneligliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Januvia is administered to a nursing woman.

• Pediatric Use

Safety and effectiveness of Januvia in pediatric patients under 18 years of age have not been established.

• Geriatric Use

Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of Januvia, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

Gender

There is no FDA guidance on the use of Teneligliptin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Teneligliptin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Teneligliptin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Teneligliptin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Teneligliptin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Teneligliptin in patients who are immunocompromised.

• Pharmacodynamics:

Teneligliptin inhibits DPP-4 which leads to increased levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), decreased levels of glucagon, and a stronger insulin response to glucose

• Pharmacokinetics:

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

Distribution: Volume of distribution: Approx 198 L. Plasma protein binding: 38%

Metabolism: Teneligliptin 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 metabolite5. The M2 metabolite is the cis isomer while the M5 metabolite is the trans isomer of the same metabolite.

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

1. https://www.uptodate.com/contents/Teneligliptin -drug-information?search=Teneligliptin &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Teneligliptin _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Teneligliptin ?type=full&mtype=generic#mechanism-of-action