Elena Menchi1, Charaf El Khattabi2, Olivier Denis3, Stéphanie Pochet2, Karim Amighi1 & Nathalie Wauthoz1
1 Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Boulevard du Triomphe, B-1050 Brussels, Belgium, Elena.Menchi@ulb.be
2 Pharmacology, Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Boulevard du Triomphe, B-1050 Brussels, Belgium
3 Immune Response, Sciensano, Rue Engeland 642, B-1180 Brussels, Belgium
Summary
Introduction. The combination of inhaled drugs used in maintenance therapy of non-communicable respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) has shown significant improvement in symptoms and pulmonary function. As the co-administration of a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) could provide synergistic benefit on airway smooth muscle relaxation, pharmacological interactions between formoterol fumarate dihydrate (FOR) and tiotropium bromide monohydrate (TIO), and indacaterol maleate (IND) and TIO were studied using an ex vivo technique. Methods. An experimental model of isolated perfused guinea pig tracheal rings was used to highlight the dose ratios generating strong synergistic interactions that could be used in the formulated combinations. Recorded data were analysed with two widely used pharmacological models, the Bliss independence (BI) theory and the unified theory. These enable the synergy to be identified by accurate statistical analysis and the magnitude of interaction to be quantified, respectively[1]. Results. Synergistic interactions were found among the dose ratios tested, with the maximum interaction magnitudes for FOR:TIO 2:1 (w/w) and IND:TIO 10:1 (w/w). Conclusion. The dose ratio showing the strongest synergy and leading to the best dose reduction when compared with the same drugs as monotherapy will be chosen to be formulated. However, this synergy at the selected dose ratio requires to be confirmed on a preclinical model of asthma or COPD by assessing lung function.
Key Message
It was proposed that dose ratios of LABA/LAMA (w/w) combinations resulting in synergistic airway relaxation were highlighted using an appropriate ex vivo model of isolated perfused guinea pig tracheal rings. This was done to optimise the benefits of the co-administration of these drugs in the treatment of asthma and COPD.