Trajenta, 30 pcs., 5 mg, film-coated tablets
The pharmacokinetics of linagliptin have been extensively studied when used in healthy volunteers and patients with type 2 diabetes mellitus. In healthy volunteers, after taking linagliptin at a dose of 5 mg, it was rapidly absorbed, the Cmax of linagliptin in plasma was reached after 1.5 hours.
The concentration of linagliptin in plasma decreases in three phases. Terminal T1/2 is long, more than 100 hours, which is mainly due to the stable binding of linagliptin to the DPP-4 enzyme, however, since the relationship is reversible, accumulation of linagliptin does not occur.
The effective T1/2 after repeated doses of linagliptin at a dose of 5 mg is approximately 12 hours. When taking linagliptin at a dose of 5 mg 1 time per day, steady-state plasma concentrations of linagliptin are achieved after the third dose.
The pharmacokinetics of linagliptin in healthy volunteers and patients with type 2 diabetes mellitus were generally similar.
Suction.
The absolute bioavailability of linagliptin is approximately 30%.
Taking linagliptin with a high-fat meal does not have a clinically significant effect on pharmacokinetics. In vitro
studies have shown that linagliptin is a substrate for P-gp and the CYP3A4 isoenzyme. Ritonavir, as a potential inhibitor of P-gp and the CYP3A4 isoenzyme, may double the AUC value. Rifampin, as a potential inducer of P-gp and the CYP3A4 isoenzyme, may reduce the AUC value during steady-state pharmacokinetics.
Distribution.
Vd after a single intravenous administration of linagliptin at a dose of 5 mg to healthy volunteers is approximately 1.11 L, indicating extensive tissue distribution. The binding of linagliptin to plasma proteins depends on its concentration and is about 99% at a concentration of 1 nmol/l, and 75–89% at a concentration of more than 30 nmol/l, which reflects the saturation of the binding of linagliptin to DPP-4 as its concentration increases. At high concentrations, when complete saturation of DPP-4 occurs, 70–80% of linagliptin is bound to other plasma proteins (not DPP-4), and 30–20% of linagliptin is in the plasma in an unbound state.
Metabolism.
Approximately 5% of linagliptin is excreted by the kidneys. A small portion of linagliptin is metabolized. Metabolism plays a minor role in the elimination of linagliptin. There is one known major metabolite of linagliptin, which has no pharmacological activity.
Excretion.
The predominant route of elimination is through the intestines. 4 days after oral administration of [14C] labeled linagliptin in healthy volunteers, approximately 85% of the dose was excreted (80% intestinal and 5% renal) with a creatinine Cl of approximately 70 ml/min.
Pharmacokinetics in special groups of patients
Kidney failure.
In patients with mild renal impairment (Cl creatinine 50 to <80 mL/min), steady-state exposure to linagliptin was comparable to exposure in healthy subjects. In moderate renal impairment (creatinine Cl 30 to <50 ml/min), a slight increase in exposure was observed (approximately 1.7 times compared with healthy subjects). Exposure to linagliptin in patients with type 2 diabetes mellitus and severe renal impairment (Cl creatinine <30 mL/min) was increased approximately 1.4-fold compared with patients with diabetes mellitus and normal renal function. Modeling of linagliptin AUC values in patients with end-stage renal disease showed that exposure in these cases was comparable to exposure in patients with moderate or severe renal impairment. The use of hemodialysis or peritoneal dialysis is not expected to eliminate linagliptin to a therapeutically significant extent. Therefore, no changes in linagliptin dosage are required in patients with any degree of renal impairment.
Liver failure.
In patients with mild, moderate, and severe hepatic impairment (Child-Pugh classification), the mean AUC and Cmax values of linagliptin after multiple doses of 5 mg were similar to those in matched healthy subjects. No dosage changes are required for linagliptin in patients with mild, moderate or severe hepatic impairment.
BMI.
No changes in linagliptin dosage are required based on BMI.
Floor.
No changes in linagliptin dosing are required depending on gender.
Elderly patients.
No age-related dosing changes for linagliptin are required as age did not have a clinically significant effect on the pharmacokinetics of linagliptin in a population pharmacokinetic analysis performed in clinical studies. Plasma concentrations of linagliptin were comparable in both older patients (age 65–80 years) and younger patients.
Children.
The pharmacokinetics of linagliptin in children has not been studied.
Race.
There are no changes in linagliptin dosing based on race. Race did not significantly influence linagliptin plasma concentrations in a combined analysis of pharmacokinetic data obtained from Caucasian, Hispanic, African American, and Asian patients. In addition, the pharmacokinetic characteristics of linagliptin were similar in special studies conducted in healthy Caucasian volunteers and residents of Japan and China, as well as in African-American patients with type 2 diabetes mellitus.
Trajenta®
In vitro assessment of drug interactions
Linagliptin is a weak competitive inhibitor of the CYP3A4 isoenzyme.
Linagliptin does not inhibit other CYP isoenzymes and is not an inducer.
Linagliptin is a substrate for P-glycoprotein and inhibits to a small extent P-glycoprotein-mediated transport of digoxin.
In vivo assessment of drug interactions
Linagliptin does not have a clinically significant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin and oral contraceptives, which has been proven in vivo, and is based on the low ability of linagliptin to lead to drug interactions with substrates for CYP3A4, CYP2C9, CYP2C8, P-glycoprotein and transport molecules of organic cations.
Metformin.
The combined use of metformin (multiple daily doses of 850 mg 3 times/day) and linagliptin at a dose of 10 mg 1 time/day (above the therapeutic dose) in healthy volunteers did not lead to clinically significant changes in the pharmacokinetics of linagliptin or metformin. Thus, linagliptin is not an inhibitor of organic cation transport.
Sulfonylurea derivatives.
The pharmacokinetics of linagliptin (5 mg) did not change when combined with glibenclamide (single dose of glyburide 1.75 mg) and repeated oral administration of linagliptin (5 mg each). However, there was a clinically insignificant decrease in the AUC and Cmax values of glibenclamide by 14%. Because glibenclamide is metabolized primarily by CYP2C9, these data also support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically significant interactions are not expected with other sulfonylureas (for example, glipizide and glimepiride), which, like glibenclamide, are mainly metabolized by CYP2C9.
Thiazolidinediones.
Co-administration of multiple doses of linagliptin 10 mg/day (above the therapeutic dose) and pioglitazone 45 mg/day (multiple doses), which is a substrate for CYP2C8 and CYP3A4, did not have a clinically significant effect on the pharmacokinetics of linagliptin or pioglitazone, or the active metabolites of pioglitazone. . This indicates that linagliptin in vivo is not an inhibitor of CYP2C8-mediated metabolism and supports the conclusion that linagliptin does not have a significant inhibitory effect on CYP3A4 in vivo.
Ritonavir.
Co-administration of linagliptin (single dose 5 mg orally) and ritonavir (multiple doses of 200 mg orally), an active inhibitor of P-glycoprotein and the CYP3A4 isoenzyme, increased the AUC and Cmax values of linagliptin by approximately 2-fold and 3-fold, respectively. However, these changes in linagliptin pharmacokinetics were not considered significant. Therefore, clinically significant interactions with other P-gp and CYP3A4 inhibitors are not expected and no dose adjustment is required.
Rifampicin.
Repeated co-administration of linagliptin and rifampicin, an active inducer of P-glycoprotein and the CYP3A4 isoenzyme, led to a decrease in the AUC and Cmax values of linagliptin by 39.6% and 43.8%, respectively, and to a decrease in the inhibition of basal dipeptidyl peptidase-4 activity by approximately 30%. Thus, the clinical efficacy of linagliptin when used in combination with active P-glycoprotein inducers is expected to be maintained, although it may not be fully realized.
Digoxin.
Combined repeated use of linagliptin (5 mg/day) and digoxin (0.25 mg/day) in healthy volunteers did not affect the pharmacokinetics of digoxin. Thus, linagliptin is not an inhibitor of P-glycoprotein-mediated transport in vivo.
Warfarin.
Linagliptin, administered repeatedly at a dose of 5 mg/day, did not change the pharmacokinetics of warfarin, which is a substrate for CYP2C9, indicating that linagliptin does not have the ability to inhibit CYP2C9.
Simvastatin.
Linagliptin, administered repeatedly to healthy volunteers at a dose of 10 mg/day (above the therapeutic dose), had minimal effect on the pharmacokinetic parameters of simvastatin, which is a sensitive substrate for CYP3A4. After taking linagliptin at a dose of 10 mg together with simvastatin, used at a daily dose of 40 mg for 6 days, the AUC value of simvastatin increased by 34%, and the Cmax value increased by 10%. Thus, linagliptin is a weak inhibitor of CYP3A4-mediated metabolism. Dose changes when taken concomitantly with drugs that are metabolized by CYP3A4 are considered inappropriate.
Oral contraceptives.
Co-administration of linagliptin at a dose of 5 mg with levonorgestrel or ethinyl estradiol did not change the pharmacokinetics of these drugs.
Description of the drug TRAZHENTA® (TRAZHENTA)
The pharmacokinetics of linagliptin have been extensively studied in healthy volunteers and in patients with type 2 diabetes mellitus. In healthy volunteers, after taking linagliptin at a dose of 5 mg, it was rapidly absorbed, the Cmax of linagliptin in plasma was reached after 1.5 hours.
The concentration of linagliptin in plasma decreases in three phases. Terminal T1/2 is long, more than 100 hours, which is mainly due to the stable binding of linagliptin to the DPP-4 enzyme, however, because the relationship is reversible, accumulation of linagliptin does not occur. The effective T1/2 after repeated doses of linagliptin at a dose of 5 mg is approximately 12 hours. When taking linagliptin at a dose of 5 mg 1 time / day, Css of linagliptin in plasma are achieved after the third dose.
The pharmacokinetics of linagliptin in healthy volunteers and in patients with type 2 diabetes mellitus was generally similar.
The absolute bioavailability of linagliptin is approximately 30%. Taking linagliptin with a high-fat meal does not have a clinically significant effect on pharmacokinetics. In vitro studies have shown that linagliptin is a substrate for P-glycoprotein and the CYP3A4 isoenzyme. Ritonavir, as a potential inhibitor of P-glycoprotein and the CYP3A4 isoenzyme, may double the AUC value. Rifampicin, as a potential inducer of P-glycoprotein and the CYP3A4 isoenzyme, may reduce the AUC value during the period of equilibrium pharmacokinetics.
Vd after a single intravenous administration of linagliptin at a dose of 5 mg to healthy volunteers is approximately 1110 L, indicating intensive tissue distribution. The binding of linagliptin to plasma proteins depends on its concentration and is about 99% at a concentration of 1 nmol/l, and 75-89% at a concentration of more than 30 nmol/l, which reflects the saturation of the binding of linagliptin to DPP-4 as its concentration increases. At high concentrations, when complete saturation of DPP-4 occurs, 70-80% of linagliptin is bound to other plasma proteins (not DPP-4), and 30-20% of linagliptin is in the plasma in an unbound state.
Approximately 5% of linagliptin is excreted by the kidneys. A small portion of linagliptin is metabolized. Metabolism plays a minor role in the elimination of linagliptin. There is one known major metabolite of linagliptin, which has no pharmacological activity.
The predominant route of elimination is through the intestines. 4 days after oral administration of [14C] labeled linagliptin in healthy volunteers, approximately 85% of the dose was excreted (80% intestinal and 5% urinary) with a clearance clearance of approximately 70 ml/min.
Trajenta 5mg n30 tab.
Composition and release form
Trajenta film-coated tablets 1 tablet contains linagliptin 5 mg Excipients: mannitol - 130.9 mg, pregelatinized starch - 18 mg, corn starch - 18 mg, copovidone - 5.4 mg, magnesium stearate - 2.7 mg. Shell composition: opadry pink (02F34337) - 5 mg (hypromellose 2910 - 2.5 mg, titanium dioxide (E171) - 1.25 mg, talc - 875 mcg, macrogol 6000 - 250 mcg, iron dye red oxide (E172) - 125 mcg). per pack 30 pcs.
pharmachologic effect
Trajenta is an oral hypoglycemic drug. Linagliptin is an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), which is involved in the inactivation of the incretin hormones glucagon-like peptide type 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones are quickly destroyed by the DPP-4 enzyme. Both of these incretins are involved in maintaining glucose concentrations at physiological levels. Basal concentrations of GLP-1 and GIP are low throughout the day and rise rapidly in response to food intake. GLP-1 and GIP enhance insulin biosynthesis and its secretion by pancreatic beta cells at normal or elevated blood glucose concentrations. In addition, GLP-1 reduces the secretion of glucagon by alpha cells of the pancreas, which leads to a decrease in glucose production in the liver. Linagliptin actively binds to the DPP-4 enzyme (the relationship is reversible), which causes a steady increase in the concentration of incretins and long-term preservation of their activity. Trajenta increases glucose-dependent insulin secretion and reduces glucagon secretion, which leads to normalization of blood glucose levels. Linagliptin binds selectively to the DPP-4 enzyme and has 10,000 times greater selectivity for DPP-4 compared to dipeptyl peptidase-8 or dipeptyl peptidase-9 enzymes in vitro.
Indications
Diabetes mellitus type 2: - as monotherapy in patients with inadequate glycemic control only due to diet and exercise, with intolerance to metformin or with a contraindication to its use due to renal failure; - as a two-component combination therapy with metformin, sulfonylurea derivatives or thiazolidinedione in case of ineffectiveness of diet therapy, exercise and monotherapy with these drugs; - as a three-component combination therapy with metformin and sulfonylurea derivatives in case of ineffectiveness of diet therapy, exercise and combination therapy with these drugs.
Category of action on the fetus
The use of linagliptin during pregnancy and breastfeeding is contraindicated. Data obtained from preclinical studies in animals indicate the penetration of linagliptin and its metabolite into breast milk. The risk of exposure to newborns and children during breastfeeding cannot be excluded. If it is necessary to use linagliptin during lactation, breastfeeding should be discontinued.
Contraindications:
— diabetes mellitus type 1; - diabetic ketoacidosis; - pregnancy; - period of breastfeeding; - children under 18 years of age; - hypersensitivity to any component of Trajenta.
Dosing
The recommended dose of Trajent is 5 mg (1 tablet) 1 time/day, orally. Trajenta can be taken with or without food at any time of the day. If you miss a regular dose, the patient should take the drug as soon as he remembers. Do not take a double dose on the same day.
Side effect
The incidence of side effects with linagliptin 5 mg was similar to the rate of side effects with placebo. Discontinuation due to adverse events was higher in the placebo group (3.6%) than in the linagliptin 5 mg group (2.3%). The following side effects were observed with linagliptin monotherapy: From the immune system: hypersensitivity. From the respiratory system: cough. From the digestive system: pancreatitis. Infectious diseases: nasopharyngitis. When using linagliptin with metformin: From the immune system: hypersensitivity. From the respiratory system: cough. From the digestive system: pancreatitis. Infectious diseases: nasopharyngitis. When using linagliptin with sulfonylurea derivatives: From the immune system: hypersensitivity. Metabolic disorders: hypertriglyceridemia. From the respiratory system: cough. From the digestive system: pancreatitis. Infectious diseases: nasopharyngitis. When using linagliptin with pioglitazone: From the immune system: hypersensitivity. Metabolic disorders: hyperlipidemia. From the respiratory system: cough. From the digestive system: pancreatitis. Infectious diseases: nasopharyngitis. Other: weight gain. When using linagliptin with metformin and sulfonylurea derivatives: From the immune system: hypersensitivity. Metabolic disorders: hypoglycemia. From the respiratory system: cough. From the digestive system: pancreatitis. Infectious diseases: nasopharyngitis.
Overdose
During controlled clinical studies in healthy volunteers, a single dose of linagliptin 600 mg (120 times the recommended dose) was well tolerated. There is no experience with the use of linagliptin in doses exceeding 600 mg. In case of overdose, it is recommended to use usual supportive measures, for example, removal of unabsorbed Trajenta from the gastrointestinal tract, clinical monitoring and symptomatic treatment.
Interaction
In vitro assessment of drug interactions Linagliptin is a weak competitive inhibitor of the CYP3A4 isoenzyme. Linagliptin does not inhibit other CYP isoenzymes and is not an inducer. Linagliptin is a substrate for P-glycoprotein and inhibits to a small extent P-glycoprotein-mediated transport of digoxin. Assessment of drug interactions in vivo Linagliptin does not have a clinically significant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin and oral contraceptives, which has been proven in vivo, and is based on the low ability of linagliptin to lead to drug interactions with substrates for CYP3A4 , CYP2C9, CYP2C8, P-glycoprotein and transport molecules of organic cations. Metformin. Combined use of metformin (multiple daily doses of 850 mg 3 times a day) and linagliptin at a dose of 10 mg 1 time a day. (above the therapeutic dose) in healthy volunteers did not lead to clinically significant changes in the pharmacokinetics of linagliptin or metformin. Thus, linagliptin is not an inhibitor of organic cation transport. Sulfonylurea derivatives. The pharmacokinetics of linagliptin (5 mg) did not change when combined with glibenclamide (single dose of glyburide 1.75 mg) and repeated oral administration of linagliptin (5 mg each). However, there was a clinically insignificant decrease in the AUC and Cmax values of glibenclamide by 14%. Because glibenclamide is metabolized primarily by CYP2C9, these data also support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically significant interactions are not expected with other sulfonylureas (for example, glipizide and glimepiride), which, like glibenclamide, are mainly metabolized by CYP2C9. Thiazolidinediones. Combined use of several doses of linagliptin 10 mg/day. (above the therapeutic dose) and pioglitazone 45 mg/day. (multiple doses), which is a substrate for CYP2C8 and CYP3A4, did not have a clinically significant effect on the pharmacokinetics of linagliptin or pioglitazone, or the active metabolites of pioglitazone. This indicates that linagliptin in vivo is not an inhibitor of CYP2C8-mediated metabolism and supports the conclusion that linagliptin does not have a significant inhibitory effect on CYP3A4 in vivo. Ritonavir. Co-administration of linagliptin (single dose 5 mg orally) and ritonavir (multiple doses of 200 mg orally), an active inhibitor of P-glycoprotein and the CYP3A4 isoenzyme, increased the AUC and Cmax values of linagliptin by approximately 2-fold and 3-fold, respectively. However, these changes in linagliptin pharmacokinetics were not considered significant. Therefore, clinically significant interactions with other P-gp and CYP3A4 inhibitors are not expected and no dose adjustment is required. Rifampicin. Repeated co-administration of linagliptin and rifampicin, an active inducer of P-glycoprotein and the CYP3A4 isoenzyme, led to a decrease in the AUC and Cmax values of linagliptin by 39.6% and 43.8%, respectively, and to a decrease in the inhibition of basal dipeptidyl peptidase-4 activity by approximately 30%. Thus, the clinical efficacy of linagliptin when used in combination with active P-glycoprotein inducers is expected to be maintained, although it may not be fully realized. Digoxin. Combined repeated use of linagliptin (5 mg/day) and digoxin (0.25 mg/day) in healthy volunteers did not affect the pharmacokinetics of digoxin. Thus, linagliptin is not an inhibitor of P-glycoprotein-mediated transport in vivo. Warfarin. Linagliptin, administered repeatedly at a dose of 5 mg/day, did not change the pharmacokinetics of warfarin, which is a substrate for CYP2C9, indicating that linagliptin does not have the ability to inhibit CYP2C9. Simvastatin. Linagliptin was used repeatedly in healthy volunteers at a dose of 10 mg/day. (above the therapeutic dose), had a minimal effect on the pharmacokinetic parameters of simvastatin, which is a sensitive substrate for CYP3A4. After taking linagliptin at a dose of 10 mg together with simvastatin, used at a daily dose of 40 mg for 6 days, the AUC value of simvastatin increased by 34%, and the Cmax value increased by 10%. Thus, linagliptin is a weak inhibitor of CYP3A4-mediated metabolism. Dose changes when taken concomitantly with drugs that are metabolized by CYP3A4 are considered inappropriate. Oral contraceptives. Co-administration of linagliptin at a dose of 5 mg with levonorgestrel or ethinyl estradiol did not change the pharmacokinetics of these drugs.
