Long-acting bronchodilators and synergistic interaction: a challenge across the currently available LABA/LAMA combinations

Abstract

Background: Long-acting β2-adrenoceptor agonists (LABAs) plus the long-acting muscarinic antagonists (LAMAs) synergistically relax human airways. However, the synergism induced by LABA/LAMA combinations have been never directly compared. Aim: We performed a pharmacological challenge across LABA/LAMA combinations by evaluating their synergistic interaction assessed via the Combination Index (CI) analysis. Methods: Aclidinium/formoterol (A/F), glycopyrronium/indacaterol (G/I), umeclidinium/vilanterol (U/V), and tiotropium/olodoaterol (T/O) combinations were administered at isoeffective concentrations to human isolated bronchi submaximally contracted by carbachol. The CI was reported at effect levels from 50% and 100% maximal effect. Results: A/F combination and U/V combination produced strong synergy (average CI: 0.107±0.01 and 0.212.9±0.018, respectively). G/I combination and T/O combination induced very strong synergy (average CI: 0.075.9±0.01 and 0.013.9±0.002, respectively). The analysis of the concentration-ratio (CR) between the monocomponents included in the approved fixed-dose combinations (FDCs) showed that G/I 50/110μg (CI 0.07 at CR ∼1:2) and T/O 5/5μg (CI 0.07 at CR ∼1:1) were balanced combinations able to produce synergistic effect. Conversely, A/F 400/12μg (CI 0.19 at CR ∼10:1) was borderline to induce synergistic interaction, and U/V 62.5/25μg (CI 0.20 at CR ∼1:300) could not elicit synergism. Conclusions: LABA/LAMA combinations can induce bronchorelaxant synergistic interaction only when administered at isoeffective concentrations. Adequate pharmacological studies are needed to find the best CR in the FDCs.