Pharmacokinetics and safety of aclidinium bromide, a muscarinic antagonist, in adults with normal or impaired renal function: A phase I, open-label, single-dose clinical trial

Schmid, Kurt; Pascual, Sílvia; Gil, Esther Garcia; Ortiz, Stephan; Jansat, Josep M.

doi:10.1016/j.clinthera.2010.09.002

Cited by 30 publications

(30 citation statements)

References 18 publications

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“…However, when LABAs were compared to tiotropium alone, the risk of myocardial infarction and other MACEs was not greater [128]. Moreover, to date, the risk of MACEs using LABA/LAMA fixed dose combinations is considered to be uncommon, if any [ Pharmacokinetics LAMA bioavailability mainly derives from the lung dose and is substantially proportional to the dose inhaled within the studied dosage ranges [111,[129][130][131]. After inhalation, all LAMAs rapidly reach peak plasma levels.…”

Section: Safetymentioning

confidence: 97%

Long-acting muscarinic antagonists

Melani

2015

Expert Review of Clinical Pharmacology

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Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Inhaled bronchodilators are the mainstay of COPD pharmacological treatment. Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators. Some LAMA/device systems with different characteristics and dosing schedules are currently approved for maintenance therapy of COPD and a range of other products are being developed. They improve lung function and patient-reported outcomes and reduce acute bronchial exacerbations with good safety. LAMAs are used either alone or associated with long-acting β₂-agonists, eventually in fixed dose combinations. Long-acting β₂-agonist/LAMA combinations assure additional benefits over the individual components alone. The reader will obtain a view of the safety and efficacy of the different LAMA/device systems in COPD patients.

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Section: Safetymentioning

confidence: 97%

Long-acting muscarinic antagonists

Melani

2015

Expert Review of Clinical Pharmacology

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“…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.…”

Section: 10mentioning

confidence: 99%

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

Kr¹,

Beck²,

D³

et al. 2016

J COPD F

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Background: Aclidinium bromide, an M 3 -receptor-selective, twice-daily (BID), long-acting muscarinic antagonist, is rapidly hydrolyzed in human plasma, resulting in low systemic exposure and urinary excretion. We evaluated the overall and cardiovascular (CV) safety of aclidinium in patients with moderate to severe chronic obstructive pulmonary disease (COPD) by pooling data from 6 randomized, double-blind, placebo-controlled, parallel-group studies of ≥1 month's duration. Methods: Patients were current/former smokers aged ≥40 years with no history of clinically significant CV conditions. Treatment was administered (morning and evening) via Genuair TM /Pressair. ®a Adverse events (AEs), major adverse CV events (MACE), cardiac and cerebrovascular AEs, and serious AEs (SAEs) were analyzed. Results: The pooled population included 2781 patients (aclidinium: n=1529; placebo: n=1252). The incidence of AEs was similar with aclidinium (53.5%) and placebo (55.4%), as was the incidence of cardiac (aclidinium: 5.0%; placebo: 4.4%) and cerebrovascular (aclidinium: 0.4%; placebo: 0.5%) events. The incidence of MACE was low (AEs: 0.7%; SAEs: 0.5%) and comparable between groups. The incidence of cardiac and cerebrovascular events was similar for patients with CV risk factors with aclidinium and placebo (rate ratio [RR] [95%confidence interval (CI)]=1.01 [.074, 1.39]). In patients with mild to severe renal impairment, the incidence of cardiac events was similar between groups (RR [95% CI]=0.87 [0.56, 1.36]). Conclusion: Aclidinium 400µg BID has a good safety profile and this pooled analysis found no evidence of increased CV or cerebrovascular risk compared with placebo in patients with moderate to severe COPD. Further studies are needed in high-risk patients. AbstractAbbreviations: twice daily, BID; cardiovascular, CV; chronic obstructive pulmonary disease, COPD; adverse event, AE; major adverse cardiovascular event, MACE; serious adverse event, SAE; rate ratio, RR; confidence interval, CI; long-acting muscarinic antagonist, LAMA; Global initiative for chronic Obstructive Lung Disease, GOLD; dry-powder inhaler, DPI; Understanding Potential Long-term Impacts on Function with Tiotropium, UPLIFT trial; TIOtropium Safety and Performance in Respimat, TIOSPIR trial; chronic kidney disease, CKD; fixed-dose combination, FDC; once daily, QD; forced expiratory volume in 1 second, FEV1; Standardized MedDRA Queries, SMQ; preferred term, PT; myocardial infarction, MI; system organ class, SOC; angiotensin-converting enzyme, ACE; calcium ion, Ca 2+ ; standard deviation, SD Funding Support: The studies included in this pooled analysis were funded by Almirall S.A., Barcelona, Spain and Forest Laboratories LLC, a subsidiary of Actavis PLC, New York, New York. The pooled analysis was funded by Almirall S.A., Barcelona, Spain.

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“…dry mouth, constipation) typically expected with the LAMA drug class. In addition, consistent with the rapid hydrolysis of aclidinium, a pharmacokinetic study in adults with normal or impaired renal function demonstrated that less than 0.1% of the mean dose of unchanged aclidinium was excreted renally in healthy subjects as well as in subjects with mild, moderate, or severe renal impairment when administered as a single inhaled 400 µg dose [Schmid et al 2010]. The low urinary excretion of aclidinium in patients across varying degrees of renal function suggests that no dose adjustment is needed for patients with renal impairment.…”

Section: Pharmacology and Pharmacokinetics Of Aclidiniummentioning

confidence: 93%

“…This is likely due to the low and transient systemic exposure of aclidinium resulting from its rapid plasma hydrolysis. As such, neither renal impairment nor advanced age affects exposure to the drug, making dose adjustment of aclidinium unnecessary in patients with impaired renal function or in elderly subjects [Schmid et al 2010;De la Motte et al 2012]. In contrast, tiotropium is excreted by the kidneys [Turck et al 2004], leading to the recommendation that patients with moderate-tosevere renal impairment be monitored closely for anticholinergic side effects [Boehringer Ingelheim Pharmaceuticals, 2011].…”

Section: Discussionmentioning

confidence: 99%

The potential for aclidinium bromide, a new anticholinergic, in the management of chronic obstructive pulmonary disease

Maltais

Milot

2012

Ther Adv Respir Dis

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Long-acting muscarinic antagonists (LAMAs) play a central role in the management of chronic obstructive pulmonary disease (COPD). Previously, only one LAMA (tiotropium) was available for the treatment of COPD, necessitating the development of other therapeutic options due to the heterogeneity of COPD and patient responses to treatment. This article reviews the COPD management potential of aclidinium bromide, a LAMA administered twice daily (BID) by a multidose dry powder inhaler that is indicated for maintenance treatment of COPD. Aclidinium possesses kinetic selectivity for the M3 versus M2 receptor and is rapidly hydrolyzed in plasma to two major inactive metabolites, resulting in a low and transient systemic exposure and minimizing the potential for systemic side effects. A pharmacokinetic study with multiple doses of twice-daily aclidinium demonstrated the short half-life of aclidinium in plasma, suggesting that a steady state may be reached as early as the second day postdose. In a phase II study, twice-daily aclidinium 400 µg provided 24-hour bronchodilation, with significant improvements versus tiotropium during the second half of the day. In two phase III studies (ACCORD I and ATTAIN), both aclidinium 200 µg and 400 µg BID provided statistically significant improvements in trough forced expiratory volume in 1 second (FEV1) and other related lung function measurements. Improvements in peak FEV1 on day 1 were comparable to those at study end, demonstrating that aclidinium provides maximal bronchodilation after the first dose that is maintained over time. Health status was significantly improved and dyspnea, nighttime and morning symptoms of COPD were likewise significantly reduced with aclidinium. Numerically greater improvements in efficacy were observed with the 400 µg dose compared with the lower dose, with similar safety profiles between the two doses and a low incidence of anticholinergic side effects. The approved therapeutic dose of aclidinium 400 µg BID is thus an effective new treatment option for patients with COPD.

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Pharmacokinetics and safety of aclidinium bromide, a muscarinic antagonist, in adults with normal or impaired renal function: A phase I, open-label, single-dose clinical trial

Cited by 30 publications

References 18 publications

Long-acting muscarinic antagonists

Long-acting muscarinic antagonists

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

The potential for aclidinium bromide, a new anticholinergic, in the management of chronic obstructive pulmonary disease

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