With the inhalation application of the combination of meiklucidinium and vilanterol, the pharmacokinetics of each compound was similar to that observed when each active substances (see subsection "Metabolism"), For this reason, the pharmacokinetics of each substance will be considered separately.
Suction
In healthy volunteers, after inhalation of vilantherol, the mean maximum concentration (FROMmax) was achieved after 5-15 minutes. Absolute bioavailability inhalation vilaterherol was 27%, taking into account the insignificant 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,max was achieved after 5-15 minutes. Absolute bioavailability inhalation lycopodium, on average, was 13%, taking into account the insignificant 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.
Distribution
After intravenous administration of vilantherol to healthy volunteers, the average volume distribution in the equilibrium state was 165 liters. Binding to human plasma proteins in vitro, on average, was 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 average, was 89%.
Metabolism
Research in vitro showed that vilaterherol is metabolized mainly under the action of the isoenzyme CYP3A4 systems cytochrome P450, and that it is a substrate of the P-glycoprotein carrier (P-gp). The main pathway of metabolism is O-dealkylation with the formation of a number of metabolites that have significantly lower beta 1 and beta 2-adrenomimetic activity. Metabolic profile of blood plasma,determined in the human body during a study using radioactive isotopes after oral administration of vilantherol, is consistent with the high metabolism of the first passage. Systemic exposure of metabolites is low.
Research in vitro showed that mukuklidiniyu is mainly under the influence of isoenzyme CYP2D6 systems of cytochrome P450. and that it is a carrier substrate P-gp. The main way of metabolism is oxidation (hydroxylation, O-dealkylation) followed by conjugation (glucuronation, etc.), leading to the formation of a number of metabolites with a lower pharmacological activity, or metabolites, pharmacological activity of which is established. Systemic exposure of such metabolites is low.
Available pharmacokinetic data obtained from a study in healthy volunteers and patients with COPD. There is no change in the system EXPOSITIONS (FROMmax and medium area under the pharmacokinetic curve (AUC)) and predicted exposure in the study 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 combined with a strong inhibitor of isoenzyme CYP3A4 - ketoconazole (400 mg) there was an increase in the mean AUC(0-1) and Cmax vilaterherol at 65 and 22%, respectively. An increase in exposure to intralesional ns resulted in an increase in the systemic effects characteristic of beta-agonists: the effect on the heart rate, potassium content in the blood or the interval QT (corrected by the method of Frederick).
Both mucocline and vilaterol are substrates P-gp. In healthy volunteers, the effect of a moderate vector inhibitor P-gp sviraamyl (240 mg once daily) on the pharmacokinetics of intrapartum and umklidiniya in the equilibrium state. Influences of the Surahamil on Cmax vilaterol or meuklikidiniya was not observed. There was an approximately 1.4-fold increase AUC muclipidinia, while AUC vilantherola has not changed.
Excretion
Plasma clearance of vilaterherol after intravenous administration was 108 l / h. 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 inhalation of vilantherol for 10 days, the half-life from the plasma was, on average, 11 hours.
Plasma clearance of muclipidinia after intravenous administration was 151 l / h. 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 the 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 a slight absorption in this route of administration. After inhalation of muclacidinia within 10 days, the half-life from plasma was, in average, 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 mocyclidine, determined in patients with COPD 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 (Cmax and AUC). There are no signs of a change in binding to proteins in patients with impaired function of the night compared to healthy volunteers.
Patients with Mr.hepatic function
In the study of patients with impaired liver function of moderate severity, no data were obtained indicating an increase in the systemic exposure of vilantherol or meuklikidinia (Cmax and AUC). There are no signs of binding changes c proteins in patients c a violation of liver function of moderate severity compared with healthy volunteers. Studies of the combination of vilaterherol and Muclikidinia in patients with severe liver failure was not performed.
Other patient groups
Population pharmacokinetics data showed no need for dose adjustment vilaterol, or muclucidinia, depending on age, race and sex, inhaled glucocorticosteroids or body weight. In the study of patients with a weak metabolic activity of the isoenzyme CYP2D6 no data were obtained indicating a clinically significant effect genetic polymorphism of the enzyme CYP2D6 to the systemic exposition of muclidinia.