Use of Propranolol Blockade to Explore the Pharmacology of GSK961081, a Bi-Functional Bronchodilator, in Healthy Volunteers: Results from Two Randomized Trials

Abstract

PurposeThe objective of this study was to explore the pharmacology of GSK961081, a bi-functional bronchodilator, in healthy volunteers.MethodsTwo randomized, double-blind, placebo-controlled studies were conducted. Following optimization of the propranolol dosing regimen (study 1), we conducted a five-period crossover study (study 2) in which subjects received the following treatments: dry powder inhaler (DPI) GSK961081 400 µg + oral placebo, DPI GSK961081 1,200 µg + oral placebo, DPI GSK961081 400 µg + oral propranolol 80 mg, DPI GSK961081 1,200 µg + oral propranolol 80 mg and DPI and oral placebo. GSK961081 (or inhaled placebo) was dosed at 0 h. Propranolol (or oral placebo) was dosed at −8, −2, 4, 10, and 16 h. The primary endpoint for both studies was bronchodilation, measured by specific airway conductance (sGaw), which was assessed at 0, 1, 4, 7, 12, 22, and 24 h in study 2. Tolerability and pharmacokinetics were secondary endpoints.ResultsStudies 1 and 2 enrolled 18 and 23 subjects, respectively. In study 2, bronchodilation was seen for 24 h following GSK961081 400 and 1,200 μg. In the presence of β2 blockade, GSK961081 1,200 μg demonstrated bronchodilation in the first 4 h after dosing (treatment difference from placebo at 1 h: 1.206; 90 % confidence interval [CI] 1.126–1.292; and at 4 h: 1.124; 90 % CI 1.078–1.173) but not at 7 h onwards. In the presence of β2 blockade, GSK961081 400 μg demonstrated bronchodilation in the first 1 h after dosing (treatment difference from placebo: 1.193; 90 % CI 1.117–1.274), but not at 4 h onwards. Adverse events were reported for 21 (study 1) and 15 subjects (study 2); none were serious, and there were no deaths.ConclusionThe duration of bronchodilation as a result of receiving the muscarinic antagonist component alone was shorter than that from the muscarinic antagonist β2 agonist combination. Removing the β2 agonist component may underestimate the contribution of the muscarinic antagonist component to the bronchodilation of the combination.

Open‐Label, Randomized, 6‐Way Crossover, Single‐Dose Study to Determine the Pharmacokinetics of Batefenterol (GSK961081) and Fluticasone Furoate When Administered Alone or in Combination

“…This was the first study in which BAT and FF have been administered as combination therapy in humans and the first time BAT has been administered using the DPI‐E. Supratherapeutic doses of BAT and FF were selected for this study to enable single‐dose PK profiles to be adequately characterized over 12 hours, and no safety issues were expected based on data from previous studies of single inhaled doses . A 12‐hour PK sampling schedule was employed, as FF and BAT plasma concentrations were expected to be at or below their respective assay LLQ by 12 hours postdose.…”

Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/β2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile

“…This was confirmed in human bronchi, where propranolol only produced a decrease in the potency of AZD8871 of 2-fold, whereas batefenterol showed a significant shift in potency of 6-fold. Our results are in agreement with published data, in which batefenterol showed about 5-fold higher potency for the b 2 -adrenoceptor than for the muscarinic receptors in in vitro studies (Hegde et al, 2014) and a noteworthy reduction in the bronchodilator effect under propranolol blockade in clinical trials (Norris and Ambery, 2014). The profile of LAS190792, a MABA compound that also reached clinical stages, is not very different from that of batefenterol, with a drop in potency in human bronchi under propranolol blockade of 5-fold (Aparici et al, 2017).…”

<p>Ultra Long-Acting β-Agonists in Chronic Obstructive Pulmonary Disease</p>

“…In healthy volunteers receiving propranolol to induce β 2 blockade, 1200 mcg of batefenterol induced bronchodilation measured by specific airway conductance at 1 and 4 h but not 7 or more hours after dosing whereas 400 mcg batefenterol stimulated bronchodilation for only the first hour after dosing. 106 These results suggest that the bronchodilatory effect of the antimuscarinic agent dissipates faster than the β-agonist effect.…”