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Sitagliptin

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2019-09-19
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Clinical Pharmacology

The drug Xelevia® (sitagliptin) is active when taken orally, a highly selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), intended for the treatment of type 2 diabetes. Sitagliptin differs in chemical structure and pharmacological action from analogs of glucagon-like peptide-1 (GLP-1), insulin, sulfonylurea derivatives, biguanides, gamma-receptor-activated gamma receptors (PPAR-γ), amylin analogs. Inhibiting DPP-4, sitagliptin increases the concentration of two hormones of the incretin family: GLP-1 and glucose-dependent insulinotropic polypeptide (HIP). Hormones of the family of incretins are secreted in the intestine during the day, their concentration increases in response to food intake. Incretins are part of the internal physiological system for regulating glucose homeostasis. At normal or elevated blood glucose concentrations, hormones of the incretin family contribute to an increase in insulin synthesis, as well as its secretion by beta cells of the pancreas due to signaling intracellular mechanisms associated with cyclic adenosine monophosphate (AMP).

GLP-1 also contributes to the suppression of increased glucagon secretion by pancreatic alpha cells. A decrease in glucagon concentration against the background of an increase in insulin concentration contributes to a decrease in glucose production by the liver, which ultimately leads to a decrease in glycemia. This mechanism of action differs from the mechanism of action of sulfonylurea derivatives, which stimulate the release of insulin and with a low concentration of glucose in the blood, which is fraught with the development of sulfon-induced hypoglycemia not only in patients with type 2 diabetes, but also in healthy individuals.

With a low blood glucose concentration, the listed effects of incretins on insulin release and a decrease in glucagon secretion are not observed. GLP-1 and HIP do not affect the release of glucagon in response to hypoglycemia. Under physiological conditions, the activity of incretins is limited by the enzyme DPP-4, which quickly hydrolyzes the incretins to form inactive products.

Sitagliptin prevents hydrolysis of incretins by the DPP-4 enzyme, thereby increasing the plasma concentrations of the active forms of GLP-1 and HIP. By increasing the concentration of incretins, sitagliptin increases glucose-dependent insulin release and helps to reduce glucagon secretion. In patients with type 2 diabetes mellitus with hyperglycemia, these changes in insulin and glucagon secretion lead to a decrease in the concentration of glycated hemoglobin HbA1C and a decrease in plasma glucose concentration, determined on an empty stomach and after a stress test.

In patients with type 2 diabetes, taking a single dose of Kselevia® leads to inhibition of the activity of DPP-4 enzyme for 24 hours, which leads to an increase in the concentration of circulating incretin GLP-1 and HIP by a factor of 2-3, and an increase in plasma insulin concentration C -peptide, reducing the concentration of glucagon in the blood plasma, reducing fasting glucose, as well as reducing glycemia after glucose load or food load.

Pharmacokinetics:

The pharmacokinetics of sitagliptin is comprehensively described in healthy individuals and patients with type 2 diabetes. In healthy individuals after oral administration of 100 mg of sitagliptin, rapid absorption of the drug is observed with the maximum concentration (Cmax) in the range from 1 to 4 hours from the moment of administration. The area under the concentration-time curve (AUC) increases in proportion to the dose and in healthy subjects is 8.52 mcmol / l * hour when taken 100 mg orally, C max was 950 nmol / l. Plasma AUC of sitagliptin increased by approximately 14% after the next dose of 100 mg of the drug to achieve an equilibrium state after taking the first dose. The intra-and intersubjective coefficients of variation of the AUC of sitagliptin were insignificant.

Absorption

The absolute bioavailability of sitagliptin is approximately 87%. Since the combined intake of sitagliptin and fatty foods does not have an effect on the pharmacokinetics, the drug Kseleviya® can be administered regardless of the meal.

Distribution

The average distribution in equilibrium after a single dose of 100 mg of sitagliptin in healthy volunteers is approximately 198 liters. The fraction of sitagliptin binding to plasma proteins is relatively low at 38%.

Metabolism

Approximately 79% of sitagliptin is excreted unchanged by the kidneys. Only a small fraction of the drug ingested is metabolized.

After the introduction of 14C-labeled sitagliptin, approximately 16% of the radioactive sitagliptin was ingested in the form of its metabolites. Traces of 6 sitagliptin metabolites, probably not having DPP-4 inhibitory activity, were found. In vitro studies have revealed that the primary isoenzymes involved in limited sitagliptin metabolism are CYP3A4 and CYP2C8.

Removal

After the introduction of 14C-labeled sitagliptin inside healthy volunteers, approximately 100% of the administered sitagliptin was eliminated: 13% through the intestines, 87% by the kidneys - within one week after taking the drug. The average half-life of sitagliptin when administered orally with 100 mg is approximately 12.4 hours; renal clearance is approximately 330 ml / min.

Sitagliptin removal is primarily carried out by excretion by the kidneys by the mechanism of active tubular secretion. Sitagliptin is a substrate for a transporter of organic human anions of the third type (hОАТ-3), which may be involved in the process of excretion of sitagliptin by the kidneys. Clinically, hOAT-3 involvement in sitagliptin transport has not been studied. Sitagliptin is also a substrate of p-glycoprotein, which can also participate in the process of excretion of sitagliptin by the kidneys. However, cyclosporine, an inhibitor of p-glycoprotein, did not reduce the renal clearance of sitagliptin.

Pharmacokinetics in certain groups of patients

Patients with renal failure

An open study of sitagliptin at a dose of 50 mg per day was conducted to study its pharmacokinetics in patients with varying degrees of severity of chronic renal failure. The patients included in the study were divided into groups of patients with mild renal insufficiency (creatinine clearance 50 to 80 ml / min), moderate (creatinine clearance 30 to 50 ml / min) and severe renal insufficiency (creatinine clearance less than 30 ml / min) and also with end-stage chronic renal failure requiring dialysis.

In patients with mild renal failure, no clinically significant change in plasma sitagliptin concentration was observed compared with the control group of healthy volunteers.

The increase in SUC of Sitagliptin by approximately two times compared with the control group was observed in patients with moderate renal insufficiency; approximately fourfold increase in AUC was observed in patients with severe renal failure, as well as in patients with end-stage chronic renal failure compared with the control group. Sitagliptin was slightly removed by hemodialysis: only 13.5% of the dose was removed from the body during the 3-4 hour dialysis session.

Thus, dose adjustment is required to achieve a therapeutic concentration of sitagliptin in plasma (similar to that in patients with normal renal function) in patients with moderate to severe renal insufficiency (see the section “Dosage and administration”).

Patients with liver failure

In patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale), the average AUC and Cmax of sitagliptin in a single dose of 100 mg increase by approximately 21% and 13%, respectively.Thus, the dose adjustment of the drug for mild and moderate liver failure is not required.

There is no clinical data on the use of sitagliptin in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale). However, due to the fact that sitagliptin is primarily excreted by the kidneys, one should not expect a significant change in the pharmacokinetics of sitagliptin in patients with severe liver failure.

Elderly patients

The age of the patients had no clinically significant effect on the pharmacokinetic parameters of sitagliptin. Compared with young patients, in elderly patients (65-80 years old), the concentration of sitagliptin is approximately 19% higher. Dose adjustment of the drug depending on age is not required.

Indications

Monotherapy

Kselevia® is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes.

Combination therapy

Combination with Metformin

Kseleviya® drug in combination with metformin is indicated for patients with type 2 diabetes mellitus to improve glycemic control as a starting therapy or when diet and exercise combined with monotherapy with one of these drugs does not lead to adequate glycemic control.

Combination with sulfonylurea derivatives

Xleevia® in combination with sulfonylurea is indicated for patients with type 2 diabetes to improve glycemic control when diet and exercise combined with monotherapy with one of the listed drugs does not lead to adequate glycemic control.

Combination with PPAR-γ agonists

Xleevia® in combination with PPAR-γ agonists (thiazolidinediones) is indicated for patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise combined with monotherapy with one of these drugs does not lead to adequate glycemic control.

Combination with metformin and sulfonylurea derivatives

Xleevia® in combination with metformin and sulfonylurea is indicated for patients with type 2 diabetes to improve glycemic control when diet and exercise combined with therapy with two of these drugs do not lead to adequate glycemic control.

Combination with Metformin and PPAR-γ Agonists

Xleevia® in combination with metformin and PPAR-γ agonists (thiazolidinediones) is indicated for patients with type 2 diabetes to improve glycemic control, when diet and exercise combined with therapy with two of these drugs do not lead to adequate glycemic control.

Insulin combination

Xleevia® is indicated for patients with type 2 diabetes as an insulin supplement (with or without metformin) in cases where diet, exercise, and a stable insulin dose do not lead to adequate glycemic control.

Composition

One tablet film coated contains:

Active ingredient: sitagliptin phosphate monohydrate 128.5 mg (equivalent to 100 mg of sitagliptin).

Excipients: microcrystalline cellulose 123.8 mg, calcium phosphate unground, 123.8 mg, croscarmellose sodium 8,000 mg, magnesium stearate 4,000 mg, sodium stearyl fumarate 12.00 mg;

Opadray® II tablet shell beige, 85F17438 (16.00 mg) contains: polyvinyl alcohol 40,000%, titanium dioxide (E 171) 21,560%, macrogol 3350 (polyethylene glycol) 20,200%, talc 14,800%, ferric oxide yellow (E 172) 3,070 % iron oxide red (E 172) 0.370%.

Sitagliptin is marketed under different brands and generic names, and comes in different dosage forms:

Brand nameManufacturerCountryDosage form
pills
Januvia Merck Sharp & Dohme USA pills

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Sitagliptin

Dosage and Administration

When used as monotherapy or in combination with metformin or a PPAR-γ agonist (for example, thiazolidinedione), the recommended dose of Januvia is 100 mg 1 time / day.
Yanuvu can be taken regardless of the meal. If the patient missed taking Januvia, the drug should be taken as soon as possible. Do not take a double dose of Januvia.
In case of mild renal failure (CC ≥50 ml / min, approximately corresponding to serum creatinine ≤ 1.7 mg / dL in men, ≤ 1.5 mg / dL in women), no dose adjustment is required.
In moderately severe renal failure (CC ≥30 ml / min, but 1.7 mg / dL, but ≤ 3 mg / dL in men,> 1.5 mg / dL, but ≤ 2.5 mg / dL in women), the dose of Januvia is 50 mg 1 times / day
In severe renal failure (KK3 mg / dl in men,> 2.5 mg / dl in women), for patients with end-stage renal failure and the need for hemodialysis, the dose of the drug Januvia is 25 mg 1 time / day. hemodialysis procedures.

Adverse reactions

On the part of the digestive system: abdominal pain, nausea, vomiting, diarrhea. Laboratory indicators: hyperuricemia, decrease in the activity of the total and partially bone fraction of alkaline phosphatase, leukocytosis due to an increase in the number of neutrophils.

Others (causal relationship with taking the drug has not been established): upper respiratory tract infections, nasopharyngitis, headache, arthralgia. The incidence of hypoglycemia is similar to that when taking placebo.

Contraindications

- Type 1 diabetes.

- Diabetic ketoacidosis.

- Pregnancy.

- Lactation period (breastfeeding).

- Hypersensitivity to the drug. It is not recommended to prescribe the drug Januia to children and adolescents under the age of 18 years (data on the use of the drug in pediatric practice is not available). Use with caution in patients with renal insufficiency. In case of moderate and severe renal failure, as well as patients with end-stage renal failure who need hemodialysis, correction of the dosing regimen is required.

Drug interactions

In studies of the interaction with other drugs, sitagliptin had no clinically significant effect on the pharmacokinetics of the following drugs: metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, oral contraceptives. Based on these data, sitagliptin does not inhibit CYP3A4, 2C8 or 2C9 isoenzymes. Based on in vitro data, sitagliptin probably does not inhibit CYP2D6, 1A2, 2C19 or 2B6, nor does it induce CYP3A4. There was a slight increase in AUC (11%), as well as an average C max (18%) of digoxin when used together with sitagliptin. This increase is not considered clinically significant. It is not recommended to change the dose of either digoxin or Januvia when used simultaneously. An increase in AUC and C max of sitagliptin was noted by 29% and 68%, respectively, in patients with a joint use of Januvia in a single dose of 100 mg and cyclosporine (a p-glycoprotein potent inhibitor) in a single dose of 600 mg. These changes in the pharmacokinetic parameters of sitagliptin are not considered clinically significant. It is not recommended to change the dose of the drug Januvia when used together with cyclosporine and other inhibitors of p-glycoprotein (for example, ketoconazole). Population pharmacokinetic analysis in patients and healthy volunteers (n = 858) who received a wide range of concomitant medications (n ​​= 83, about half of which are excreted by the kidneys), did not reveal any clinically significant effect of drugs on the pharmacokinetics of sitagliptin.

Pregnancy and Lactation

Adequate and strictly controlled clinical studies of the safety of the drug Januvia in pregnant women was not conducted. The use of the drug during pregnancy is contraindicated.It is not known whether sitagliptin is excreted in human breast milk. If necessary, the use of the drug during lactation should decide on the termination of breastfeeding.

Special instructions

In clinical studies of the drug Januvia as monotherapy or as part of combination therapy with metformin or pioglitazone, the incidence of hypoglycemia with the use of the drug Januvia was similar to the incidence of hypoglycemia with placebo. The combined use of the drug Januvia in combination with drugs that can cause hypoglycemia, such as insulin, sulfonylurea derivatives, has not been studied.
Patients with mild and moderate hepatic insufficiency do not require dose adjustment of the drug Januvia.
In clinical studies, the efficacy and safety of the drug Januvia in elderly patients (≥65 years, 409 patients) were comparable with these indicators in patients younger than 65 years. Dose adjustment for age is not required. Elderly patients are more likely to develop renal failure. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal insufficiency.
 

Overdosage

Symptoms: During clinical studies on healthy volunteers, good tolerance was observed when taking Januvia in a single dose of 800 mg. Minimal changes in the QTc interval, not considered clinically significant, were noted in one of the studies of the drug at the indicated dose. Clinical studies of the drug in a dose of more than 800 mg / day was not conducted.

Treatment: removal of an unabsorbed drug from the gastrointestinal tract, monitoring of vital signs, including an ECG, and, if necessary, symptomatic and supportive therapy. Sitagliptin is poorly dialyzed. In clinical studies, only 13.5% of the dose was removed from the body during the 3-4 hour dialysis session. Prolonged dialysis can be prescribed with in case of clinical need. There is no data on the effectiveness of peritoneal dialysis of sitagliptin.

  • Brand name: Xelevia
  • Active ingredient: Sitagliptin
  • Dosage form: Film Coated Tablets
  • Manufacturer: Bayer Pharma AG

Studies and clinical trials of Sitagliptin (Click to expand)

  1. Herstellung von Sitagliptin: ein Paradebeispiel für die Prozessoptimierung
  2. Dose-proportionality of a final market image sitagliptin formulation, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers
  3. Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers
  4. Sensitive liquid chromatography tandem mass spectrometry method for the quantification of sitagliptin, a DPP-4 inhibitor, in human plasma using liquid–liquid extraction
  5. ChemInform Abstract: Highly Efficient Asymmetric Synthesis of Sitagliptin.
  6. ChemInform Abstract: The Asymmetric Synthesis of Sitagliptin, a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes.
  7. ChemInform Abstract: Sitagliptin Manufacture: A Compelling Tale of Green Chemistry, Process Intensification, and Industrial Asymmetric Catalysis
  8. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus
  9. Evaluation of the interaction between sitagliptin and cyclodextrin derivatives by capillary electrophoresis and nuclear magnetic resonance spectroscopy
  10. Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin
  11. Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: Close analogs of JANUVIA™ (sitagliptin phosphate)
  12. A practical synthesis of trifluorophenyl R-amino acid: The key precursor for the new anti-diabetic drug sitagliptin
  13. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: Results from two randomized, double-blind, placebo-controlled studies with single oral doses
  14. PII-49Lack of clinically significant effect of moderate hepatic insufficiency on the pharmacokinetics of MK-0431 (sitagliptin), a dipeptidyl-peptidase-IV (DPP-IV) inhibitor
  15. PIII-17Effect of a single cyclosporine a (NEORAL™) dose on the single-dose pharmacokinetics (PK) of sitagliptin (MK-0431), a dipeptidyl peptidase-IV inhibitor (DPP-IV), in healthy male subjects
  16. PIII-60Effect of renal insufficiency on the pharmacokinetics of MK-0431 (sitagliptin), a selective dipeptidyl-peptidase-IV (DPP-IV) inhibitor
  17. PIII-64Multiple dose administration of MK-0431 (sitagliptin), an inhibitor of dipeptidyl peptidase-IV, does not meaningfully alter the plasma pharmacokinetics or pharmacodynamics of single doses of warfarin
  18. Determination of sitagliptin in human urine and hemodialysate using turbulent flow online extraction and tandem mass spectrometry
  19. Simultaneous quantitation of metformin and sitagliptin from mouse and human dried blood spots using laser diode thermal desorption tandem mass spectrometry
  20. Enhancement of hematopoietic stem cell engraftment by inhibition of CXCL12 proteolysis with sitagliptin, an oral dipeptidyl-peptidase IV inhibitor: A report in a case of delayed graft failure
  21. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes
  22. Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis
  23. Rhinorrhea, cough and fatigue in patients taking sitagliptin
  24. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus

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