Vipidia [Alogliptin]

Aogliptin is a potent and highly selective DPP-4 inhibitor. Its selectivity for DPP-4 is more than 10,000 times greater than its effect for other related enzymes, including DPP-8 and DPP-9. DPP-4 is the main enzyme involved in the rapid destruction of the hormones of the incretin family: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (HIP).
Hormones of the family of incretins are secreted in the intestine, their concentration increases in response to food intake. GLP-1 and HIP increase insulin synthesis and its secretion by beta cells of the pancreas. GLP-1 also inhibits glucagon secretion and decreases the production of glucose by the liver. Therefore, by increasing the concentration of incretins, alogliptin increases glucose-dependent insulin secretion and decreases glucagon secretion with an increased concentration of glucose in the blood. 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 HbA_1cand a decrease in plasma glucose concentration in both fasting and postprandial glucose.

Pharmacokinetics
The pharmacokinetics of alogliptin is similar in healthy individuals and in patients with type 2 diabetes.
Suction
Absolute bioavailability of alogliptin is approximately 100%. Simultaneous intake with high-fat foods did not affect the area under the concentration-time curve (AUC) of alogliptin, so it can be taken regardless of the meal. In healthy individuals, after a single oral dose of up to 800 mg of alogliptin, rapid absorption of the drug is observed, with an average maximum concentration (mean TC_max.) in the range from 1 to 2 hours from the moment of reception.
Neither healthy volunteers nor patients with type 2 diabetes mellitus showed a clinically significant cumulation of alogliptin after repeated administration.
AUC of alogliptin increases proportionally with a single dose in the therapeutic range of doses from 6.25 mg to 100 mg. The variability of AUC of alogliptin among patients is small (17%). The AUC (O-inf) alogliptin after a single dose was similar to the AUC (0-24) after taking the same dose once a day for 6 days. This indicates the absence of a time dependence in the kinetics of alogliptin after repeated administration.
Distribution
After a single intravenous injection of alogliptin at a dose of 12.5 mg in healthy volunteers, the volume of distribution in the terminal phase was 417 liters, which indicates that alogliptin is well distributed in the tissues. Communication with plasma proteins is approximately 20-30%.
Metabolism
Aogliptin is not subjected to intensive metabolism, from 60 to 70% of alogliptin is excreted unchanged by the kidneys.
After the introduction ¹⁴There were two major metabolites identified with C-labeled alogliptin: N-demethylated alogliptin, MI (In vitro studies revealed that CYP2D6 and CYP3A4 are involved in the limited metabolism of alogliptin.
Also, in vitro studies show that alogliptin does not induce CYP1A2, CYP2C9, CYP2B6 and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 in concentrations achieved at a recommended dose of 25 mg of alopttin. In vitro, alogliptin may induce CYP3A4 to a small extent; however, in vivo, alogliptin does not induce CYP3A4.
Aogliptin does not inhibit the renal transporters of organic human anions of the first (OAT1), third (OATP) types and the renal transporters of organic human cations of the second (OCT2) type.
Aogliptin exists mainly in the form of (11) -enantiomer (> 99%) and in in vivo or in small quantities, or not at all undergoes chiral transformation into (8) -enantiomer. (8) -enantiomer is not detectable when taking alogliptin in therapeutic doses.
Removal
After oral administration ¹⁴C-labeled alogliptin 76% of the total radioactivity was excreted by the kidneys and 13% through the intestines. The average renal clearance of alogliptin (170 ml / min) is greater than the average glomerular filtration rate (about 120 ml / min), which suggests that alogliptin is partially excreted due to active renal excretion. The average terminal half-life of alogliptin (T½) is approximately 21h.
Pharmacokinetics in certain groups of patients
Patients with renal failure
The study of alogliptin 50 mg per day was conducted in patients with varying degrees of severity of chronic renal failure. The patients included in the study were divided into 4 groups according to the Cockroft-Gault formula: patients with mild (creatinine clearance 50 to 80 ml / min), moderate severity (creatinine clearance 30 to 50 ml / min) and severe renal failure (creatinine clearance less than 30 ml / min), as well as patients with end-stage chronic renal failure who need hemodialysis.
AUC of alogliptin in patients with mild renal insufficiency increased approximately 1.7 times compared with the control group. However, this increase in AUC was within the tolerance limits for the control group, therefore, dose adjustment in these patients is not required (see Dosage and Administration). An increase in the AUC of alogliptin about two times compared with the control group was observed in patients with moderately severe renal failure. 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. (Patients with end-stage renal disease underwent hemodialysis immediately after ingesting alogliptin. About 7% of the dose was removed from the body during the 3-hour dialysis session.)
Thus, in order to achieve therapeutic plasma concentrations of alogliptin, similar to that in patients with normal renal function, dose adjustment is necessary in patients with moderately severe renal insufficiency (see Dosage and Administration). Aogliptin is not recommended for patients with severe renal insufficiency, as well as with end-stage renal failure requiring hemodialysis.
Patients with liver failure
In patients with moderate severity of liver failure AUC and C_max. Alohliptin decreases by approximately 10% and 8%, respectively, compared with patients with normal liver function. These values ​​are not clinically significant. Thus, the dose adjustment of the drug with mild and moderate severity of liver failure (from 5 to 9 points on the Child-Pugh scale) is not required. There are no clinical data on the use of alogliptin in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale, see Dosage and Administration).
Other patient groups
Age (65-81 years), gender, race, body weight of the patients did not have a clinically significant effect on the pharmacokinetic parameters of alogliptin. Dose adjustment of the drug is not required (see. Dosage and administration).
Pharmacokinetics in children under 18 have not been studied.