Chemical formula: C₁₉H₂₈NO₃+ Molecular mass: 318.431 g/mol PubChem compound: 9933193
Glycopyrronium is a quaternary ammonium antimuscarinic with peripheral effects similar to those of atropine.
Antimuscarinics are competitive inhibitors of the actions of acetylcholine at the muscarinic receptors of autonomic effector sites innervated by parasympathetic (cholinergic postganglionic) nerves. They also inhibit the action of acetylcholine where smooth muscle lacks cholinergic innervation.
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.
Salivation is primarily mediated by parasympathetic innervation of the salivary glands. Glycopyrronium competitively inhibits cholinergic muscarinic receptors in salivary glands and other peripheral tissues, thus indirectly reducing the rate of salivation. Glycopyrronium has little effect on cholinergic stimuli at nicotinic acetylcholine receptors, on structures innervated by postganglionic cholinergic neurons, and on smooth muscles that respond to acetylcholine but have no cholinergic innervation.
Peripheral antimuscarinic effects that are produced as the dose increases are: decreased production of secretions from the salivary, bronchial and sweat glands; dilatation of the pupils (mydriasis) and paralysis of accommodation (cyclopegia); increased heart rate; inhibition of micturition and reduction in gastrointestinal tone; inhibition of gastric acid secretion.
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 the inhaler in contrast to the half life after intravenous administration.
Mean absolute oral bioavailability of glycopyrronium comparing a single 50 μg/kg oral dose and a single 5 μg/kg intravenous dose was low at approximately 3% (range 1.3–13.3%) in children aged 7-14 years undergoing intraocular surgery (n=6) due to the medicinal product’s low lipid solubility. Data from sparse PK sampling in children suggests dose proportional PK.
The bioavailability of oral glycopyrronium in children was between that of adults under fed and fasted conditions.
Following oral inhalation using the inhaler, glycopyrronium was rapidly absorbed and reached peak plasma levels at 5 minutes post dose.
The absolute bioavailability of glycopyrromium inhaled 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.
In adults, distribution of glycopyrronium was rapid following a single 6 μg/kg intravenous dose; distribution half-life was 2.2 ± 1.3 minutes. Following administration of 3H-labelled glycopyrronium more than 90% of the radiolabel disappeared from the plasma in 5 minutes, and almost 100% within 30 minutes, reflecting rapid distribution. Analyses of population pharmacokinetic data from healthy adults and children with cerebral palsy-associated chronic moderate to severe drooling who received glycopyrronium (route of administration and doses not specified) did not demonstrate linear pharmacokinetics of the medicinal product.
The volume of distribution, 0.64 ± 0.29 L/kg in adults is similar to that of total body water. Volume of distribution is somewhat higher in the paediatric population(s), in the range 1.31 to 1.83 L/kg.
The PK of glycopyrronium has been shown to be essentially independent of age in children in the age range 0.19 – 14 years administered a 5 μg/kg intravenous single-dose. In most paediatric subjects, plasma glycopyrronium vs. time plots are reported to show a triexponential curve; adults generally show a biexponential curve. Modest changes in volume of distribution (Vss) and clearance (Cl) have been observed in children between 1 and 3 years of age, leading to a statistically significant shorter elimination half-life (t½,z) than that observed in younger (<1 year of age; p=0.037) or older (>3 years of age; p=0.042) groups.
In a study in healthy adults, a 2000 μg single dose of glycopyrronium bromide resulted in an AUC of 2.39 μg.h/L (fasted). An AUC0-6h of 8.64 μg.h/L was observed after 6 μg/kg intravenous glycopyrronium.
Based upon theoretical physicochemical considerations, the quaternary ammonium compound glycopyrronium would be expected to have low central bioavailability; no glycopyrronium was detectable in the CSF of anaesthetised surgical patients or patients undergoing caesarean section following a 6–8 μg/kg intravenous dose. In the paediatric population 5 μg/kg intravenous glycopyrronium has low central bioavailability, except in the case where the blood brain barrier has been compromised (e.g. a shunt infection).
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.
The primary route of elimination of glycopyrronium is via renal excretion, mainly as unchanged medicinal product. Approximately 65% of an intravenous dose is renally excreted within the first 24 hours. A small proportion (~5%) is eliminated in the bile.
The elimination half-life of glycopyrronium appears to be dependent on route of administration being 0.83 ± 0.27 hours after intravenous administration, 75 minutes after intramuscular administration and in the region of 2.5-4 h after oral (solution) administration, though again this was highly variable.
That the latter two half-lives, and especially that for oral administration, are longer than for intravenous administration probably reflects the complex absorption and distribution of glycopyrronium by each route. It is possible that prolonged absorption after oral administration translates into elimination being faster than absorption (known as flip-flop kinetics, characterized by Ka < Ke).
The total body clearance of the medicinal product following an intravenous dose is relatively high at between 0.54 ± 0.14 L/h/kg and 1.14 ± 0.31 L/h/kg. As this exceeds the glomerular filtration rate and it appears that more than 50% of the dose is excreted unchanged in the urine, it is probable that the renal elimination of glycopyrronium involves both glomerular filtration and proximal tubular secretion by the base secretory mechanism.
A mean increase in total systemic exposure (AUClast) of up to 1.4 fold was seen in adult subjects with mild and moderate renal impairment (GFR ≥30mL/min/1.73m²) and up to 2.2 fold in subjects with severe renal impairment or end stage renal disease (estimated GFR <30 mL/min/1.73m²). A 30% dose reduction is required for patients with mild to moderate renal impairment. Glycopyrronium is contraindicated in patients with severe renal impairment.
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.
Impaired hepatic function is not expected to affect the pharmacokinetics of glycopyrronium since the majority of the medicinal product is eliminated through the kidneys.
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/1.73 m²) glycopyrronium can be used at the recommended dose. In patients with severe renal impairment (eGFR <30 ml/min/1.73 m²), including those with end-stage renal disease requiring dialysis, glycopyrronium should only be used if the expected benefit outweighs the potential risk.
Baseline characteristics (age, weight, gender and race) do not affect the pharmacokinetics of glycopyrronium.
Co-administration with food results in a marked decrease in systemic glycopyrronium exposure.
Non-clinical data, including genotoxicity or carcinogenicity studies have not been performed for Sialanar.
Limited non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology or repeated dose toxicity.
The single dose toxicity of glycopyrronium has been tested in a range of investigations, although only limited experimental details are available. Upon oral administration, high LD50 values of 550 mg/kg in mice and above 1,000 mg/kg in rats were reported. In rats at higher doses (1500-2000 mg/kg) tremors, clonic and tonic convulsions and laboured breathing were observed prior to death, resulting from respiratory failure.
Chronic oral administration of glycopyrronium at doses of 4, 16 and 64 mg/kg for up to 27 weeks in dogs produced mydriasis, cycloplegia, xerostomia, emesis, occasional lacrimation, injection of sclera and rhinorrhoea.
Extrapolation of safety margins to the paediatric population is not possible, as no exposure data are available from repeated dose toxicology studies and no studies in juvenile animals have been performed with glycopyrronium.
Data on reproductive endpoints for glycopyrronium are very limited. A reduction in corpora lutea was observed in female rats administered glycopyrronium. No effects on fertility were observed in male rats. Reproductive performance in rats given glycopyrronium shows a decrease in the rate of conception and in survival rate at weaning. The significance of the non-clinical findings for humans is not clear, and the lack of human data on the medicinal product leads to glycopyrronium being contraindicated in pregnant women. There are insufficient data in the public domain to adequately assess effects on the reproductive system in young adults, and safety in human pregnancy has not been established.
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.
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