With the inhalation application of the combination of meuklikidiniya and vilanterol, the pharmacokinetics of each compound was similar to that observed when each active ingredient was used separately. For this reason, the pharmacokinetics of each substance will be considered separately.
Suction
In healthy volunteers after inhalation of vilantherol, the average maximum concentration of the substance in the blood plasma was achieved in 5-15 minutes. Absolute bioavailability of inhalation vilaterherol averaged 27%, taking into account the very slight absorption of the substance in the oral cavity. After repeated inhalations of vilaterherol, an equilibrium state with a 2.4-fold accumulation was achieved after 6 days.
In healthy volunteers after inhalation, muclacodynia the maximum concentration of the substance in the blood plasma was achieved in 5-15 minutes.Absolute bioavailability of inhalation muclipidinia averaged 13%, taking into account the very slight absorption of the substance in the oral cavity. After repeated inhalations of meuklikidiniya in 7-10 days, an equilibrium state was achieved with a 1.5-2 fold accumulation. After inhalation of 113 μg of muclucidinia, its systemic exposure was approximately twice as high as that observed after inhalation of the drug at a dosage of 55 μg.
Distribution
After intravenous administration of vilantherol to healthy volunteers, the average volume of distribution in the equilibrium state was 165 liters. Binding to human plasma proteins in vitro on the average it is equal to 94%.
After intravenous injection of meuklikidiniya to healthy volunteers, the average volume of distribution was 86 liters. Binding to human plasma proteins in vitro on the average is 89%.
Metabolism
Research in vitro have shown that vilaterherol is metabolized mainly under the action of the CYP3A4 isoenzyme of the cytochrome P450 system and that it is the substrate of the P-glycoprotein (P-gp) carrier. The main pathway of metabolism is O-dealkylation with the formation of a number of metabolites that have a significantly lower beta1- and beta2-adrenomimetic activity.The metabolic profile of blood plasma, determined in the human body during a study using radioactive isotopes after oral intake of vilaterherol, is consistent with the high metabolism of the "first passage". Systemic exposure of metabolites is negligible.
Research in vitro showed that smuklinidinium is metabolized mainly under the action of the CYP2D6 isoenzyme of the cytochrome P450 system and that it is the substrate of the P-gp transporter. The main way of metabolism of meuklikidiniya is oxidation (hydroxylation, O-dealkylation) followed by conjugation (glucuronation, etc.), leading to the formation of a number of metabolites with lower pharmacological activity or metabolites whose pharmacological activity has not been established. Systemic exposure of such metabolites is low.
Available pharmacokinetic data obtained from studies in healthy volunteers and patients with chronic obstructive pulmonary disease indicate no changes in systemic exposure (maximum plasma concentration and the average area under the pharmacokinetic curve (AUC)) and the predicted exposure atstudy of the population pharmacokinetics of vilantherol and meuklikidiniya when they are used together compared to similar indicators obtained with the use of both components separately. When the strong inhibitor of the isoenzyme CYP3A4-ketoconazole (400 mg) was combined, an increase in the mean AUC(0-1) and maximum concentration in blood plasma vilaterherol at 65 and 22%, respectively. An increase in the exposure of vilantherol did not lead to an increase in the systemic effects characteristic of beta-agonists: the effect on heart rate, potassium content in the blood, or the QT interval (corrected by the Frederick method).
Both mucocline and vilaterol are substrates of P-gp. In healthy volunteers, the effect of a moderate inhibitor of P-gp verapamil (240 mg once daily) on the pharmacokinetics of vilaterherol and equilibration in equilibrium was determined. Effects of verapamil on maximum concentration in blood plasma vilaterol or meuklikidiniya was not observed. There was an approximately 1.4-fold increase area under the pharmacokinetic curve muclipidinia, while area under the pharmacokinetic curve vilantherola has not changed.
Excretion
The plasma clearance of Vilanterol after intravenous administration was 108 liters per hour. After oral administration of radiolabeled tolantherol, the mass balance showed that 70% of the radioactive substance was excreted by the kidneys and 30% by the intestine. The excretion of vilantherol was mainly metabolic, followed by excretion of metabolites by the kidneys and intestines. After inhalations of vilantherol for 10 days, the half-life from plasma was an average of 11 hours.
Plasma clearance of muclipidinia after intravenous administration was 151 liters per hour. 192 hours after intravenous administration, about 58% of the dose of a substance labeled with a radioactive isotope (or 73% of the released radioactive substance) was excreted by the intestine, indicating the secretion of this compound in bile. 22% of the dose of a substance labeled with a radioactive isotope (27% of the released radioactive substance) was withdrawn by the kidneys, after 168 hours. 168 hours after the oral administration of the drug in healthy men, the bulk of the radioactive substance was excreted primarily by the intestine (92% of the dose taken by a substance labeled with a radioactive isotope or 99% of the radioactive substance isolated).With oral administration of kidneys, less than 1% of the dose of the substance (1% of the released radioactive substance) is excreted, indicating very little absorption in this route of administration. After repeated inhalations of meuklikidinia within 10 days, the half-life from the plasma averaged 19 hours, while from 3 to 4% of the unchanged substance was excreted by the kidneys in an equilibrium state.
Special patient groups
Elderly patients
Population pharmacokinetic analysis showed the similarity of the pharmacokinetics of vilantherol and muclidinia, defined in patients with chronic obstructive pulmonary disease in the age group 65 years and older and in the age group under the age of 65 years.
Patients with impaired renal function
In the study of patients with severe renal dysfunction, no data were obtained indicating an increase in the systemic exposure of vilantherol or meuklikidinia (maximum concentration in blood plasma and area under the pharmacokinetic curve). There are no signs of changes in protein binding in patients with impaired renal function compared to healthy volunteers.
Impaired liver function
In the study of patients with moderate impairment of liver function, no data were obtained indicating an increase in the systemic exposure of vilantherol or meuklikidinia (maximum concentration in blood plasma and the area under the pharmacokinetic curve). There are no signs of changes in binding to proteins in patients with impaired liver function compared to healthy volunteers. Studies of the combination of vilantherol and meuklikidiniya in patients with severe impairment of liver function were not performed.
Other patient groups
Data from the population analysis of pharmacokinetics showed no need for correction of the dose of vilaterherol or meuklikidiniya depending on age, race and sex, the use of inhaled glucocorticosteroids or body weight. In the study of patients with a weak metabolic activity of the CYP2D6 isoenzyme, no data were obtained indicating a clinically significant effect of the genetic polymorphism of the CYP2D6 isoenzyme on the systemic exposure of muclidinia.