Sitagliptin

When ATH:
A10BH01

Pharmacological action

Selective inhibitor of the dipeptidyl peptidase 4 (DDP-4). The chemical structure and pharmacological action different from other. hypoglycemic PM. Ingibiruya GMP-4, sitagliptin increases the concentration of incretin hormones family: GLP-1 and glucose-dependent insulinotropic peptide (GIP), It is part of the internal system of regulation of glucose homeostasis. Incretins are secreted into the intestine, concentration is increased in response to a meal. In normal or elevated blood glucose concentration incretins enhance insulin synthesis, and its secretion from the beta cells of the pancreas due to intracellular signaling mechanisms, associated with cyclic AMP. GLP-1 suppresses glucagon secretion increased alpha cells of the pancreas. Reducing glucagon accompanied by increased insulin concentration reduces hepatic glucose production, which ultimately leads to reduction of glycemic. Incretins not affect the synthesis of insulin and glucagon secretion in response to hypoglycemia. Under physiological conditions, the DPP-4 enzyme hydrolyses the incretins into inactive products. Sitagliptin, ingibiruya ferment GMP-4, suppresses the hydrolysis of incretin, increasing the concentration of the active form of GLP-1 and GIP, increases the release of insulin and decreases the secretion of glucagon. In diabetes 2 type hyperglycemia, these changes lead to a decrease in the concentration of glycated Hb and reduce plasma glucose concentration, determined on an empty stomach and after stress test. A single dose inhibits enzyme DPP-4 for 24 no, increases in the concentration of circulating incretins 2-3.

Pharmacokinetics

Absorbed quickly, regardless of the meal (fatty food has no effect on the pharmacokinetics of). The absolute bioavailability - 87%. Cmax — 950 nmol, TCmax - 1-4. AUC дозозависима — 8,52 mmol × h (at a dose 100 mg), It has low variability between patients. Upon reaching equilibrium readmission dose 100 mg increases the AUC by 14%. The volume of distribution - 198 l (after a single dose 100 mg). Contact proteins - 38%. A small portion of the drug is metabolized; the process involves enzymes CYP3A4 and CYP2C8. Found 6 metabolites, that do not possess the DPP-4 inhibition activity. Renal clearance - 350 ml / min. Sitagliptin is a substrate for human organic anion transporter of the third type and P-glycoprotein, that may be involved in the renal elimination of the drug. T1/2 — 12,4 no. Displayed within 1 weeks after ingestion: kishechnika (13%), kidneys by tubular secretion (79% - Unchanged, 16% - As metabolites). In patients with chronic renal failure in QA - 50-80 ml / min sitagliptin plasma concentration does not change. When QA - 30-50 ml / min indicated a 2-fold increase in AUC as compared to the control group. At least QC 30 ml / min, as well as in patients with ESRD indicated 4-fold increase in AUC. In patients with CC - 30-50 ml / min and less QC 30 ml / min to achieve a therapeutic concentration of the drug dose adjustment is required. When liver failure 7-9 points on the scale of Child-Pyuga, AUC and Cmax increased by 21% and 13% respectively (when receiving 100 mg). When liver failure more 9 points on the scale of Child-Pyuga significant changes in the pharmacokinetics are not going, tk. the drug is primarily excreted by the kidneys. Patients 65-80 years the concentration of sitagliptin up 19% (not clinically significant).

Testimony

Diabetes 2 type: as monotherapy (as an adjunct to diet and exercise) or in a combination therapy with metformin or a thiazolidinedione agonist, a peroxisome proliferator.

Contraindications

Hypersensitivity, diabetes 1 type, diabetic ketoacidosis, pregnancy, lactation, childhood and adolescence (to 18 years).

FROM caution. CRF (moderate, heavy, end stage to the need for hemodialysis).

Dosage regimen

Inside, regardless of the meal, by 100 mg 1 once daily in monotherapy, in combination with metformin or a thiazolidinedione. If you missed taking the drug, you must immediately take medication, as soon as the patient remembers. Do not assume receiving a double dose.

When QA - 30-50 ml / min, plasma creatinine 1.7-3 mg / dL (males), 1,52.5 mg / dl (female) the dose is reduced to 50 mg 1 once a day.

At least QC 30 ml / min, plasma creatinine more 3 mg / dL (males) and more 2,5 mg / dL (female), as well as for patients in end-stage chronic renal failure, requiring hemodialysis, dose of 25 mg 1 once a day (regardless of the time for dialysis).

Side effect

From the digestive system: abdominal pain, nausea, vomiting, diarrhea.

Laboratory findings: hyperuricemia, the overall decrease in activity and some bone-alkaline phosphatase, leukocytosis, due to the increase in the number of neutrophils.

Other (a causal relationship to drug intake is not installed): upper respiratory tract infection, nazofaringit, headache, arthralgia. The incidence of hypoglycaemia was similar to that of placebo.

Overdose

Symptoms: minor changes of QTc.

Treatment: removal of unabsorbed drug from the gastrointestinal tract, monitoring of vital signs (including an electrocardiogram), simptomaticheskaya therapy, if necessary - prolonged dialysis (within 3-4 hours of the session removed 13,5% dose).

Drug Interactions

There was a slight increase in AUC (on 11%), and the average Cmax (on 18%) digoxin when used with sitagliptin, that does not require correction of their dose.

Cyclosporine (potent inhibitor of P-glycoprotein) increases in AUC and Cmax of sitagliptin on 29% and 68% respectively, in the combined use 100 mg sitagliptin and 600 mg of cyclosporine (orally), that does not require dose adjustments (incl. when used with other. P-glycoprotein inhibitor ketoconazole).