title: Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model.
abstract: 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.
authors.affiliation: Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trifilieff
authors.affiliation: Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Ethell
authors.affiliation: Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom; School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Sykes
authors.affiliation: Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Kenny J
authors.initials: KJ
authors.lastname: Watson
authors.affiliation: Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Collingwood
authors.affiliation: Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom; School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, United Kingdom.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
authors.affiliation: Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom. Electronic address: tobykent@me.com.
authors.forename: Toby C
authors.initials: TC
authors.lastname: Kent
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D006024:Glycopyrrolate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D011485:Protein Binding; D011869:Radioligand Assay; D011914:Rats, Inbred BN; D043585:Receptor, Muscarinic M2 / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D000069447:Tiotropium Bromide
chemical_list: D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D012602:Scopolamine Derivatives; D006024:Glycopyrrolate; D000069447:Tiotropium Bromide
keywords: COPD; Cardiovascular; Glycopyrronium; Muscarinic; Respiratory; Tiotropium