The in vitro and in vivo profile of aclidinium bromide in comparison with glycopyrronium bromide

Abstract

This study characterised the in vitro and in vivo profiles of two novel long-acting muscarinic antagonists, aclidinium bromide and glycopyrronium bromide, using tiotropium bromide and ipratropium bromide as comparators. All four antagonists had high affinity for the five muscarinic receptor sub-types (M1-M5); aclidinium had comparable affinity to tiotropium but higher affinity than glycopyrronium and ipratropium for all receptors. Glycopyrronium dissociated faster from recombinant M3 receptors than aclidinium and tiotropium but more slowly than ipratropium; all four compounds dissociated more rapidly from M2 receptors than from M3 receptors. In vitro, aclidinium, glycopyrronium and tiotropium had a long duration of action at native M3 receptors (>8 h versus 42 min for ipratropium). In vivo, all compounds were equi-potent at reversing acetylcholine-induced bronchoconstriction. Aclidinium, glycopyrronium and ipratropium had a faster onset of bronchodilator action than tiotropium. Aclidinium had a longer duration of action than glycopyronnium (time to 50% recovery of effect [t½ offset] = 29 h and 13 h, respectively); these compare with a t½ offset of 64 h and 8 h for tiotropium and ipratropium, respectively. Aclidinium was less potent than glycopyrronium and tiotropium at inhibiting salivation in conscious rats (dose required to produce half-maximal effect [ED50] = 38, 0.74 and 0.88 μg/kg, respectively) and was more rapidly hydrolysed in rat, guinea pig and human plasma compared with glycopyrronium or tiotropium. These results indicate that while aclidinium and glycopyrronium are both potent antagonists at muscarinic receptors with similar kinetic selectivity for M3 receptors versus M2, aclidinium has a longer dissociation half-life at M3 receptors and a longer duration of bronchodilator action in vivo than glycopyrronium. The rapid plasma hydrolysis of aclidinium, coupled to its kinetic selectivity, may confer a reduced propensity for systemic anticholinergic side effects with aclidinium versus glycopyrronium and tiotropium.

Overall and Cardiovascular Safety of Aclidinium Bromide in Patients With COPD: A Pooled Analysis of Six Phase III, Placebo-Controlled, Randomized Studies

“…12 Preclinical and pharmacological studies with aclidinium have demonstrated low systemic availability and a low propensity to induce cardiac arrhythmias, 11-13 and these findings have been reflected in a safety and tolerability profile that is similar to placebo in larger clinical trials. [14][15][16][17][18][19] Due to the rapid hydrolysis of aclidinium in plasma, the kidney plays little role in clearance of the drug and urinary excretion is very low.…”

Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits

“…Nevertheless, we are confident that investigations performed on healthy preparations can provide useful insights into the regulation of the cough reflex as well as hints for further studies on this reflex and possibly for the development of novel antitussive strategies. Preclinical studies have indicated that aclidinium may have a faster onset of action than tiotropium, but comparable protective effects on bronchoconstriction [32,33]. In addition, since it has been reported that the clinical dose of tiotropium 18 mg is very low with respect to the clinical dose of aclidinium 400 mg [14], we made an attempt to find the isoeffective dose of the two drugs as far as bronchodilation is concerned.…”

“…In addition, since it has been reported that the clinical dose of tiotropium 18 mg is very low with respect to the clinical dose of aclidinium 400 mg [14], we made an attempt to find the isoeffective dose of the two drugs as far as bronchodilation is concerned. The potency of these two LAMAs has been previously assessed in guinea pigs [32,33]. Aclidinium 100 mg/mL and tiotropium 10 mg/mL produced 1 h post-administration equi-effective (97e98%) inhibition of acetylcholine-induced bronchoconstriction that lasted several hours.…”

“…Ninety min after drug inhalation, the MCh challenge was repeated and R L re-evaluated. The interval of 90 min was chosen to ensure LAMA maximum effects; both aclidinium and tiotropium (as other LAMAs) have been proved to fully express their protective action on cholinergic-induced bronchoconstriction at least 1 h post-administration [32]. As illustrated in Fig.…”

“…The stimulation protocol was repeated at appropriate intervals (~5 min for mechanical stimulation and 10e15 min for citric acid inhalation) for about further 120 min to follow the recovery process. No attempt was made to investigate the recovery process for longer time periods owing to the very long-lasting duration of drug-induced effects [32]. All stimulation procedures were performed at least 5e6 min after each supplemental dose of pentobarbital to avoid its possible immediate influence on the recorded variables.…”