Umeclidinium

Breast Feeding; Lactation; Milk, Human; Parasympatholytics; Muscarinic Antagonists; Bronchodilator Agents

EMA approved medicines: Human medicine

Antiasthmatic and medicines for chronic obstructive pulmonary disease

QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled, crossover trial in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent. In humans, the M3 receptor has been heavily implicated in the pathophysiology of asthma and COPD. Once the M3 receptor is activated, the phospholipase C would phosphorylate downstream targets, forming inositol 1,4,5-trisphosphate and eventually releasing intracellular Ca²⁺. Increase in intracellular Ca²⁺ results in muscle contraction, thus worsening COPD and asthma-related bronchoconstriction. Additionally, M3 receptor activation also regulates pathways involving CD38, cyclic ADP ribose (cADPR), and ryanodine receptor channels, all of which control the intracellular Ca²⁺ homeostasis that will lead to muscle contraction.

Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect.

In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), 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.