Umeclidinium Other names: Umeclidinium bromide

Umeclidinium bromide is a long acting muscarinic receptor antagonist (also referred to as an anticholinergic). It is a quinuclidine derivative that is a muscarinic receptor antagonist with activity across multiple muscarinic cholinergic receptor subtypes. Umeclidinium bromide exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic cholinergic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models.

Pharmacodynamic effects

In a Phase III, 6-month study (DB2113373) umeclidinium bromide provided a clinically meaningful improvement over placebo in lung function (as measured by forced expiratory volume in 1 second [FEV₁]) over 24 hours following once daily administration, which was evident at 30 minutes following administration of the first dose (improvement over placebo by 102 mL, p<0.001*). The mean peak improvements in FEV₁ within the first 6 hours following dosing relative to placebo were 130 ml (p<0.001*) at Week 24. There was no evidence for tachyphylaxis in the effect of umeclidinium bromide over time.

^* A step-down statistical testing procedure was used in this study and this comparison was below a comparison that did not achieve statistical significance. Therefore, statistical significance on this comparison cannot be inferred.

Cardiac electrophysiology

The effect of umeclidinium 500 micrograms (pre-dispensed) on the QT interval was evaluated in a placebo- and moxifloxacin-controlled QT trial of 103 healthy volunteers. Following repeat doses of umeclidinium 500 micrograms once daily for 10 days, no clinically relevant effect on prolongation of QT interval (corrected using the Fridericia method) or effects on heart rate were observed.

Absorption

Following inhaled administration of umeclidinium bromide in healthy volunteers, C_max occurred at 5 to 15 minutes. The absolute bioavailability of inhaled umeclidinium bromide was on average 13% of the dose, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium bromide, steady state was achieved within 7 to 10 days with 1.5 to 1.8-fold accumulation.

Distribution

Following intravenous administration to healthy subjects, the mean volume of distribution was 86 litres. In vitro plasma protein binding in human plasma was on average 89%.

Biotransformation

In vitro studies showed that umeclidinium bromide is principally metabolised by cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium bromide are oxidative (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Elimination

Plasma clearance following intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose (or 73% of the recovered radioactivity) was excreted in faeces by 192 hours post-dose. Urinary elimination accounted for 22% of the administered radiolabelled dose by 168 hours (27% of recovered radioactivity). The excretion of the material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration to healthy male subjects, total radioactivity was excreted primarily in faeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168 hours post-dose. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration. Umeclidinium bromide plasma elimination half-life following inhaled dosing for 10 days averaged 19 hours, with 3% to 4% active substance excreted unchanged in urine at steady-state.

Special populations

Elderly

A population pharmacokinetic analysis showed that pharmacokinetics of umeclidinium bromide are similar between COPD patients 65 years or older and those younger than 65 years of age.

Renal impairment

Subjects with severe renal impairment (creatinine clearance <30mL/min) showed no evidence of an increase in systemic exposure to umeclidinium bromide (C_max and AUC), and no evidence of altered protein binding between subjects with severe renal impairment and healthy volunteers.

Hepatic impairment

Subjects with moderate hepatic impairment (Child-Pugh Class B) showed no evidence of an increase in systemic exposure to umeclidinium bromide (C_max and AUC), and no evidence of altered protein binding between subjects with moderate hepatic impairment and healthy volunteers. Umeclidinium bromide has not been evaluated in subjects with severe hepatic impairment.

Other special populations

A population pharmacokinetic analysis showed that no dose adjustment is required for umeclidinium bromide based on the effect of age, race, gender, inhaled corticosteroid use or weight. A study in CYP2D6 poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium bromide.

Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In nonclinical studies with umeclidinium bromide, findings were those typically associated with the primary pharmacology of muscarinic receptor antagonists and/or local irritancy.

Toxicity to reproduction

Umeclidinium bromide was not teratogenic in rats or rabbits. In a pre- and post-natal study, subcutaneous administration of umeclidinium bromide to rats resulted in lower maternal body weight gain and food consumption and slightly decreased pre-weaning pup body weights in dams given 180 micrograms/kg/day dose (approximately 80-times the human clinical exposure of umeclidinium 55 micrograms, based on AUC).