In Vivo Pharmacological Characterization of TD-4208, a Novel Lung-Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models

Abstract

Tiotropium is currently the only once-daily, long-acting muscarinic antagonist (LAMA) approved in the United States and other countries for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrronium has shown promise as a LAMA and was recently approved for once-daily maintenance treatment of COPD in the European Union. Here, we describe the in vivo preclinical efficacy and lung selectivity of a novel inhaled muscarinic antagonist, TD-4208 (biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester) and compare its profile to tiotropium and glycopyrronium. In anesthetized dogs, TD-4208, along with tiotropium and glycopyrronium, produced sustained inhibition of acetylcholine-induced bronchoconstriction for up to 24 hours. In anesthetized rats, inhaled TD-4208 exhibited dosedependent 24-hour bronchoprotection against methacholineinduced bronchoconstriction. The estimated 24-hour potency (expressed as concentration of dosing solution) was 45.0 mg/ml. The bronchoprotective potencies of TD-4208 and tiotropium were maintained after 7 days of once-daily dosing, whereas glycopyrronium showed a 6-fold loss in potency after repeat dosing. To assess systemic functional activity using a clinically relevant readout, the antisialagogue effect of compounds was also evaluated. The calculated lung selectivity index (i.e., ratio of antisialagogue and bronchoprotective potency) of TD-4208 was superior to glycopyrronium after both single and repeat dosing regimens and was superior to tiotropium after repeat dosing. In conclusion, the in vivo preclinical profile suggests that TD-4208 has the potential to be a long-acting bronchodilator for once-daily treatment of respiratory diseases. Its greater functional selectivity for the lung in preclinical models may translate to an improved tolerability profile compared with marketed muscarinic receptor antagonists.

Revefenacin: First Global Approval

“…In vitro, revefenacin antagonized muscarinic acetylcholine cholinergic receptor-mediated contractions for up to 24 h in rat and guinea pig tracheal tissues, as well as in human airway muscle tissues [ 9 ]. In anesthetized dogs and rats, single or repeated dosing (once daily for 7 days) of inhaled revefenacin provided a dose-dependent bronchoprotection against acetylcholine- or methacholine-induced bronchoconstriction [ 10 ]. The bronchoprotective effect was seen as early as 5 min post-dose and was sustained for up to 24 h. In these animal models, repeated once daily dosing of revefenacin also exhibited superior functional lung selectivity index over repeated dosing of tiotropium (i.e.…”

“…twice daily LAMA therapy). After repeated dosing, the bronchoprotective potency of revefenacin and tiotropium was maintained, unlike glycopyrronium [ 10 ].…”

Pharmacological properties of revefenacin (TD‐4208), a novel, nebulized long‐acting, and lung selective muscarinic antagonist, at human recombinant muscarinic receptors and in rat, guinea pig, and human isolated airway tissues

“…In a previous study, we demonstrated that inhaled revefenacin produced potent protection against ACh or MCh evoked bronchoconstriction in dogs and rats . In this study, we investigated the antagonist potency and offset time in isolated tracheal tissues from rat in order to gain mechanistic insight into the long‐acting bronchoprotective effects observed in rats in vivo.…”

“…Revefenacin (TD‐4208; biphenyl‐2‐ylcarbamic acid 1‐(2‐{[4‐(4‐carbamoylpiperidin‐1‐ylmethyl)benzoyl]methylamino}ethyl)piperidin‐4‐yl ester) (Figure ) is an investigational LAMA, in late‐stage development as a nebulized inhalation solution, that was designed to produce long‐acting bronchodilation, consistent with once‐daily dosing, and with a high degree of lung‐selectivity to avoid systemic antimuscarinic adverse effects such as dry mouth, urinary retention, and constipation . Following inhalation dosing to rats and dogs, revefenacin produced potent protection against the bronchoconstrictor response to ACh or methacholine (MCh) . In both species, the bronchoprotective effect was long‐acting (≥24 hours) and comparable in duration to tiotropium.…”

Revefenacin, a Long‐Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo‐ and Positive‐Controlled Thorough QT Study

“…1 Revefenacin (YUPELRI R ) inhalation solution, delivered via standard jet nebulization, is an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). [2][3][4] After inhaled administration, revefenacin is rapidly absorbed, with peak concentrations observed within 14 to 31 minutes after the start of nebulization. Absolute bioavailability after oral administration is low (<3%).…”