Sitagliptin

Sitagliptin is a Dipeptidyl Peptidase 4 (DPP-4) Inhibitor belonging to pharmacology class of Antidiabetic.

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

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

Sitagliptin is available in the form of Tablets.

The molecule is available in India, USA, Japan, Germany.

Inhibition of DPP-4 by sitagliptin slows DPP-4 mediated inactivation of incretins like GLP-1 and GIPIncretins 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 dependant 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 Sitagliptin 1-4 hours.

Sitagliptin is available in Tablets.

Oral: Administer without regard to meals.

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

Sitagliptin inhibits dipeptidyl peptidase-4 (DPP-4) enzyme resulting in prolonged active incretin levels. Incretin hormones (eg, 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.

Sitagliptin 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: Dosage: The typical starting dose of sitagliptin for most adults is 100 milligrams (mg) once daily. However, your doctor may adjust the dose based on your individual needs and response to the medication.

Timing: Sitagliptin is usually taken once daily with or without food. You can take it in the morning or evening, but try to take it at the same time each day to help you remember.

Tablet Form: Sitagliptin is available in tablet form. Swallow the tablet whole with a full glass of water. Do not crush or chew the tablet.

Tablets

25 mg, 50 mg, 100 mg.

Tablet

• Dose Adjustment in Kidney impairment patient:

Oral:

Altered kidney function:

eGFR ≥45 mL/minute/1.73 m²: No dosage adjustment necessary.

eGFR ≥30 to <45 mL/minute/1.73 m²: 50 mg once daily.

eGFR <30 mL/minute/1.73 m²: 25 mg once daily.

Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable (13.5% removed during 3- to 4-hour hemodialysis session) :25 mg once daily; may administer without regard to timing of dialysis.

Peritoneal dialysis: 25 mg once daily.

• 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.

Sitagliptin may be contraindicated in the following conditions:-

● Serious hypersensitivity (eg, anaphylaxis, angioedema) to sitagliptin 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 sitagliptin 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 Sitagliptin in concurrent use with alcohol.

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

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin 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.

Sitagliptin 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.

Sitagliptin 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 sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours post-dose. Placental transfer of sitagliptin 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 Sitagliptin 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 Sitagliptin 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 Sitagliptin 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 sitagliptin 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
• Sitagliptin 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.
• Sitagliptin 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 sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours post-dose. Placental transfer of sitagliptin 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 Sitagliptin during labor and delivery.

Nursing Mothers

• 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. Because many drugs are excreted in human milk, caution should be exercised when Sitagliptin is administered to a nursing woman.
  

Pediatric Use

• Safety and effectiveness of Sitagliptin 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 Sitagliptin, 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 Sitagliptin with respect to specific gender populations.

Race

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

Renal Impairment

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

Hepatic Impairment

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

Females of Reproductive Potential and Males

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

Immunocompromised Patients

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

Pharmacodynamics:

Sitagliptin 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: 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.

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

Metabolism: Sitagliptin is mostly not metabolized, 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 carbamylated 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 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.

1. https://www.uptodate.com/contents/Sitagliptin -drug-information?search=Sitagliptin &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/Sitagliptin _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Sitagliptin ?type=full&mtype=generic#mechanism-of-action