Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

• Published in: Toxicology and applied pharmacology Vol. 287; no. 1; pp. 9 - 16
• Main Authors: Trifilieff, Alexandre, Ethell, Brian T., Sykes, David A., Watson, Kenny J., Collingwood, Steve, Charlton, Steven J., Kent, Toby C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.08.2015
• Subjects: 60 APPLIED LIFE SCIENCES; Airway Resistance - drug effects; Animals; Blood Pressure - drug effects; Bradycardia - chemically induced; Bradycardia - physiopathology; BROMIDES; Bronchial Provocation Tests; Bronchoconstriction - drug effects; Bronchodilator Agents - administration & dosage; Bronchodilator Agents - blood; Bronchodilator Agents - pharmacokinetics; Bronchodilator Agents - toxicity; Cardiovascular; Cardiovascular System - drug effects; Cardiovascular System - physiopathology; CHARGES; COMPARATIVE EVALUATIONS; COPD; DISEASES; DOSES; Glycopyrrolate - administration & dosage; Glycopyrrolate - blood; Glycopyrrolate - pharmacokinetics; Glycopyrrolate - toxicity; Glycopyrronium; Heart Rate - drug effects; HYPOTENSION; Hypotension - chemically induced; Hypotension - physiopathology; IN VIVO; INHIBITION; Male; Models, Biological; Muscarinic; Muscarinic Antagonists - administration & dosage; Muscarinic Antagonists - blood; Muscarinic Antagonists - pharmacokinetics; Muscarinic Antagonists - toxicity; PATIENTS; Protein Binding; Radioligand Assay; RATS; Rats, Inbred BN; Receptor, Muscarinic M2 - drug effects; Receptor, Muscarinic M2 - metabolism; RECEPTORS; Respiratory; Risk Assessment; SAFETY; Scopolamine Derivatives - administration & dosage; Scopolamine Derivatives - blood; Scopolamine Derivatives - pharmacokinetics; Scopolamine Derivatives - toxicity; SIDE EFFECTS; THERAPY; Tiotropium; Tiotropium Bromide; Tiotropium; Respiratory; Muscarinic; Cardiovascular; Glycopyrronium; COPD
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.05.012

Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1h; >200 fold at 6h) than with tiotropium (1.5 and 4.2 fold at 1h; 4.6 and 5.5 fold at 6h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M2 muscarinic receptor occupancy, which predicted significantly higher M2 receptor blockade at ED50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. •We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists.•We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate.•At ED50 doses for bronchoprotection we model systemic M2 receptor occupancy.•Glycopyrrolate demonstrates lower M2 occupancy at bronchoprotective doses.•Glycopyrrolate demonstrates an improved CV safety profile, versus tiotropium.