Vipidia (tablets)
The pharmacokinetics of alogliptin are similar in healthy individuals and in patients with type 2 diabetes mellitus.
Suction
The absolute bioavailability of alogliptin is approximately 100%.
Coadministration with a high-fat meal did not affect the area under the concentration-time curve (AUC) of alogliptin, so it can be taken without regard to meals.
In healthy individuals, after a single oral dose of up to 800 mg of alogliptin, rapid absorption of the drug is observed, reaching the average maximum concentration (average TCmax.) within 1 to 2 hours from the moment of administration.
Neither healthy volunteers nor patients with type 2 diabetes mellitus experienced clinically significant accumulation of alogliptin after repeated dosing.
The AUC of alogliptin increases proportionally with a single dose in the therapeutic dose range from 6.25 mg to 100 mg. The variability of alogliptin AUC among patients is small (17%).
The AUC (0-inf) of alogliptin after a single dose was similar to the AUC (0-24) after taking the same dose once daily for 6 days. This indicates that there is no time dependence in the kinetics of alogliptin after repeated dosing.
Distribution
After a single intravenous dose of 12.5 mg of alogliptin in healthy volunteers, the volume of distribution in the terminal phase was 417 L, indicating that alogliptin is well distributed in tissues.
The binding to plasma proteins is approximately 20-30%.
Metabolism
Alogliptin is not subject to extensive metabolism; 60 to 70% of alogliptin is excreted unchanged by the kidneys.
Following oral administration of 14C-labeled alogliptin, two major metabolites were identified: N-demethylated alogliptin, MI (˂ 1% parent material), and N-acetylated alogliptin, M-II (˂ 6% parent material). MI is an active metabolite and highly selective DPP-4 inhibitor, similar in action to alogliptin itself; M-II does not exhibit inhibitory activity against DPP-4 or other DPP enzymes.
in vitro studies
CYP2D6 and CYP3A4 were found to be involved in the limited metabolism of alogliptin.
Also in vitro
show that alogliptin does not induce CYP1A2, CYP2C9, CYP2B6 or inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at concentrations achieved at the recommended 25 mg dose of alogliptin.
In vitro,
alogliptin may induce CYP3A4 to a small extent, but in vivo, alogliptin does not induce CYP3A4. Alogliptin does not inhibit human renal transporters of organic anions of the first (OAT1), third (OAT3) types and renal human organic cation transporters of the second (OST2) type.
Alogliptin exists predominantly as the ®-enantiomer (>99%) and, in vivo, undergoes little or no chiral conversion to the (S)-enantiomer. The (S)-enantiomer is not detected when alogliptin is taken in therapeutic doses.
Removal
After oral administration of 14C-labeled alogliptin, 76% of the total radioactivity was excreted by the kidneys and 13% by the intestines.
The mean renal clearance of alogliptin (170 ml/min) is greater than the mean glomerular filtration rate (about 120 ml/min), suggesting that alogliptin is partially eliminated by active renal excretion. The average terminal half-life of alogliptin (T1/2) is approximately 21 hours.
Pharmacokinetics in selected patient groups
Patients with kidney failure
A study of alogliptin at a dose of 50 mg per day was conducted in patients with varying degrees of severity of chronic renal failure. Patients included in the study were divided into 4 groups according to the Cockcroft-Gault formula: patients with mild (creatinine clearance from 50 to 80 ml/min), moderate (creatinine clearance from 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 requiring hemodialysis.
The AUC of alogliptin in patients with mild renal impairment increased approximately 1.7-fold compared to controls. However, this increase in AUC was within the acceptable deviation for the control group, so dose adjustment of the drug is not required in such patients (see Dosage and Administration).
An approximately two-fold increase in the AUC of alogliptin compared to the control group was observed in patients with moderate renal failure. An approximately fourfold increase in AUC was observed in patients with severe renal impairment and in patients with end-stage renal disease compared with controls. (Patients with end-stage renal disease underwent hemodialysis immediately after taking alogliptin. About 7% of the dose was removed from the body during the 3-hour dialysis session.)
Thus, to achieve therapeutic plasma concentrations of alogliptin similar to those in patients with normal renal function, dose adjustment is necessary in patients with moderate renal insufficiency (see Dosage and Administration). Alogliptin is not recommended for use in patients with severe renal failure or end-stage renal disease requiring hemodialysis.
Patients with liver failure
In patients with moderate severity of liver failure, AUC and Cmax. alogliptin are reduced by approximately 10% and 8%, respectively, compared with patients with normal liver function. These values are not clinically significant. Thus, dose adjustment of the drug is not required for mild to moderate liver failure (from 5 to 9 points on the Child-Pugh scale). There are no clinical data on the use of alogliptin in patients with severe liver failure (more than 9 points on the Child-Pugh scale, see Dosage and Administration).
Other patient groups
Age (65-81 years), gender, race, and body weight of patients did not have a clinically significant effect on the pharmacokinetic parameters of alogliptin. No dose adjustment is required (see Dosage and Administration).
Pharmacokinetics in children under 18 years of age have not been studied.
Vipidia, 28 pcs., 12.5 mg, film-coated tablets
The pharmacokinetics of alogliptin are similar in healthy individuals and patients with type 2 diabetes mellitus.
Suction
The absolute bioavailability of alogliptin is approximately 100%. Concomitant administration with a high-fat meal did not affect the AUC of alogliptin, so it can be taken without regard to meals. In healthy individuals, after a single oral dose of up to 800 mg of alogliptin, rapid absorption of the drug is observed with the average Cmax achieved within 1 to 2 hours from the moment of administration.
Neither healthy volunteers nor patients with type 2 diabetes mellitus experienced clinically significant accumulation of alogliptin after repeated dosing.
The AUC of alogliptin increases proportionally with a single dose in the therapeutic dose range from 6.25 to 100 mg. The intrapatient variability of alogliptin AUC is small (17%). The AUC0-inf of alogliptin after a single dose was similar to the AUC0-24 after the same dose was administered once daily for 6 days. This indicates that there is no time dependence in the kinetics of alogliptin after repeated dosing.
Distribution
After a single intravenous administration of alogliptin at a dose of 12.5 mg in healthy volunteers, Vd in the terminal phase was 417 L, indicating good distribution in tissues. Plasma protein binding is approximately 20–30%.
Metabolism
Alogliptin is not subject to extensive metabolism; 60 to 70% of alogliptin is excreted unchanged by the kidneys.
Following oral administration of 14C-labeled alogliptin, two major metabolites were identified: N-demethylated alogliptin, M1 (<1% parent material), and N-acetylated alogliptin, M2 (<6% parent material). M1 is an active metabolite and highly selective DPP-4 inhibitor, similar in action to alogliptin itself; M2 does not exhibit inhibitory activity against DPP-4 or other DPP enzymes.
in vitro studies
CYP2D6 and CYP3A4 were found to be involved in the limited metabolism of alogliptin.
Also in vitro
show that alogliptin does not induce CYP1A2, CYP2C9, CYP2B6 or inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at concentrations achieved at the recommended 25 mg dose of alogliptin.
In vitro,
alogliptin may induce CYP3A4 to a small extent, but in
vivo,
alogliptin does not induce CYP3A4.
Alogliptin does not inhibit human renal organic anion transporters ( Organic Anion Transporters)
, OAT1), third (OAT3) types and renal transporters of human organic cations of the second (
Organic Cation Transporters
, OCT2) type.
Alogliptin exists predominantly as the (R)-enantiomer (>99%) and in vivo
or undergoes little or no chiral conversion to the (S)-enantiomer. The (S)-enantiomer is not detected when alogliptin is taken in therapeutic doses.
Removal
After oral administration of 14C-labeled alogliptin, 76% of the total radioactivity was excreted by the kidneys and 13% by the intestines. The mean renal clearance of alogliptin (170 ml/min) is greater than the mean GFR (about 120 ml/min), suggesting that alogliptin is partially eliminated through active renal excretion. The average terminal T1/2 of alogliptin is approximately 21 hours.
Selected patient groups
Kidney failure.
A study of alogliptin at a dose of 50 mg/day was conducted in patients with varying degrees of severity of chronic renal failure. Patients included in the study were divided into 4 groups according to the Cockcroft-Gault formula: patients with mild (creatinine clearance from 50 to 80 ml/min), moderate (creatinine clearance from 30 to 50 ml/min) and severe degrees of renal failure ( Cl creatinine less than 30 ml/min), as well as patients with end-stage chronic renal failure requiring hemodialysis.
The AUC of alogliptin in patients with mild renal impairment increased approximately 1.7-fold compared to the control group. However, this increase in AUC was within the acceptable deviation for the control group, so dose adjustment of the drug is not required in such patients (see "Dosage and Administration"). An approximately two-fold increase in the AUC of alogliptin compared to the control group was observed in patients with moderate renal failure. An approximately fourfold increase in AUC was observed in patients with severe renal failure and end-stage renal failure compared with controls. Patients with end-stage renal disease underwent hemodialysis immediately after taking alogliptin. About 7% of the dose was removed from the body during a 3-hour dialysis session.
Thus, to achieve therapeutic plasma concentrations of alogliptin similar to those in patients with normal renal function, dose adjustment is necessary in patients with moderate renal insufficiency (see "Dosage and Administration"). Alogliptin is not recommended for use in patients with severe renal failure or end-stage renal disease requiring hemodialysis.
Liver failure.
In patients with moderate hepatic impairment, the AUC and Cmax of alogliptin are reduced by approximately 10% and 8%, respectively, compared to patients with normal hepatic function. These values are not clinically significant. Thus, dose adjustment of the drug is not required for mild to moderate liver failure (from 5 to 9 points on the Child-Pugh scale). There are no clinical data on the use of alogliptin in patients with severe liver failure (more than 9 points on the Child-Pugh scale, see “Dosage and Administration”).
Other patient groups.
Age (65–81 years), gender, race, and body weight of patients did not have a clinically significant effect on the pharmacokinetic parameters of alogliptin. No dose adjustment of the drug is required (see “Method of administration and dosage”). Pharmacokinetics in children under 18 years of age have not been studied.
