Chemical formula: C₁₉H₂₈NO₃+ Molecular mass: 318.431 g/mol PubChem compound: 9933193
Glycopyrronium is an inhaled long-acting muscarinic receptor antagonist (anticholinergic) for once-daily maintenance bronchodilator treatment of COPD. Parasympathetic nerves are the major bronchoconstrictive neural pathway in airways, and cholinergic tone is the key reversible component of airflow obstruction in COPD. Glycopyrronium works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells, thereby dilating the airways.
Glycopyrronium bromide is a high affinity muscarinic receptor antagonist. A greater than 4-fold selectivity for the human M3 receptors over the human M2 receptor has been demonstrated using radioligand binding studies. It has a rapid onset of action as evidenced by observed receptor association/dissociation kinetic parameters and the onset of action after inhalation in clinical studies.
The long duration of action can be partly attributed to sustained concentrations of active substance in the lung as reflected by the prolonged terminal elimination half-life of glycopyrronium after inhalation via inhaler in contrast to the half life after intravenous administration.
Following oral inhalation, glycopyrronium was rapidly absorbed and reached peak plasma levels at 5 minutes post dose.
The absolute bioavailability of glycopyrromium inhaled via inhaler was estimated to be about 45% of the delivered dose. About 90% of systemic exposure following inhalation is due to lung absorption and 10% is due to gastrointestinal absorption.
In patients with COPD, pharmacokinetic steady-state of glycopyrronium was reached within one week of the start of treatment. The steady-state mean peak and trough plasma concentrations of glycopyrronium for a 44 micrograms once-daily dosing regimen were 166 picograms/ml and 8 picograms/ml, respectively. Steady-state exposure to glycopyrronium (AUC over the 24-hour dosing interval) was about 1.4- to 1.7-fold higher than after the first dose.
After intravenous dosing, the steady-state volume of distribution of glycopyrronium was 83 litres and the volume of distribution in the terminal phase was 376 litres. The apparent volume of distribution in the terminal phase following inhalation was almost 20-fold larger, which reflects the much slower elimination after inhalation. The in vitro human plasma protein binding of glycopyrronium was 38% to 41% at concentrations of 1 to 10 nanograms/ml.
In vitro metabolism studies showed consistent metabolic pathways for glycopyrronium bromide between animals and humans. Hydroxylation resulting in a variety of mono-and bis-hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9) were seen. In vivo, M9 is formed from the swallowed dose fraction of inhaled glycopyrronium bromide.
Glucuronide and/or sulfate conjugates of glycopyrronium were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.
Multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium. Inhibition or induction of the metabolism of glycopyrronium is unlikely to result in a relevant change of systemic exposure to the active substance.
In vitro inhibition studies demonstrated that glycopyrronium bromide has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrronium bromide for cytochrome P450 isoenzymes, or for UGT1A1 and the transporters MDR1 and MRP2.
After intravenous administration of [3H]-labelled glycopyrronium bromide to humans, the mean urinary excretion of radioactivity in 48 hours amounted to 85% of the dose. A further 5% of the dose was found in the bile.
Renal elimination of parent drug accounts for about 60 to 70% of total clearance of systemically available glycopyrronium whereas non-renal clearance processes account for about 30 to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.
Mean renal clearance of glycopyrronium following inhalation was in the range of 17.4 and 24.4 litres/h. Active tubular secretion contributes to the renal elimination of glycopyrronium. Up to 23% of the delivered dose was found in urine as parent drug.
Glycopyrronium plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life was much longer after inhalation (33 to 57 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration. The elimination pattern suggests sustained lung absorption and/or transfer of glycopyrronium into the systemic circulation at and beyond 24 hours after inhalation.
In COPD patients both systemic exposure and total urinary excretion of glycopyrronium at pharmacokinetic steady state increased about dose-proportionally over the dose range of 44 to 176 micrograms.
A population pharmacokinetic analysis of data in COPD patients identified body weight and age as factors contributing to inter-patient variability in systemic exposure. Glycopyrronium 44 micrograms once daily can be safely used in all age and body weight groups.
Gender, smoking status and baseline FEV1 had no apparent effect on systemic exposure.
There were no major differences in total systemic exposure (AUC) between Japanese and Caucasian subjects following inhalation of glycopyrronium bromide. Insufficient pharmacokinetic data is available for other ethnicities or races.
Clinical studies have not been conducted in patients with hepatic impairment. Glycopyrronium is cleared predominantly from the systemic circulation by renal excretion. Impairment of the hepatic metabolism of glycopyrronium is not thought to result in a clinically relevant increase of systemic exposure.
Renal impairment has an impact on the systemic exposure to glycopyrronium bromide. A moderate mean increase in total systemic exposure (AUClast) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment and up to 2.2-fold in subjects with severe renal impairment and end-stage renal disease. In COPD patients with mild and moderate renal impairment (estimated glomerular filtration rate, eGFR ≥30 ml/min/1.73m²) glycopyrronium can be used at the recommended dose. In patients with severe renal impairment (eGFR <30 ml/min/1.73m²), including those with end-stage renal disease requiring dialysis, glycopyrronium should only be used if the expected benefit outweighs the potential risk.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Effects attributable to the muscarinic receptor antagonist properties of glycopyrronium bromide included mild to moderate increases in heart rate in dogs, lens opacities in rats and, reversible changes associated with reduced glandular secretions in rats and dogs. Mild irritancy or adaptive changes in the respiratory tract were seen in rats. All these findings occurred at exposures sufficiently in excess of those anticipated in humans.
Glycopyrronium was not teratogenic in rats or rabbits following inhalation administration. Fertility and pre- and post-natal development were not affected in rats. Glycopyrronium bromide and its metabolites did not significantly cross the placental barrier of pregnant mice, rabbits and dogs. Glycopyrronium bromide (including its metabolites) was excreted into the milk of lactating rats and reached up to 10-fold higher concentrations in the milk than in the blood of the dam.
Genotoxicity studies did not reveal any mutagenic or clastogenic potential for glycopyrronium bromide. Carcinogenicity studies in transgenic mice using oral administration and in rats using inhalation administration revealed no evidence of carcinogenicity at systemic exposures (AUC) of approximately 53-fold higher in mice and 75-fold higher in rats than the maximum recommended dose of 44 micrograms once daily for humans.
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