Pharmacologic rationale, efficacy and safety of the fixed-dose co-formulation of indacaterol and glycopyrronium

Abstract

Chronic obstructive pulmonary disease (COPD) is a widespread respiratory disorder, usually characterized by progressive and poorly reversible airflow limitation. Inhaled long-acting bronchodilators, namely LABA (long-acting β2-adrenergic agonists) and LAMA (long-acting muscarinic receptor antagonists) are the mainstay of COPD treatment. Because the symptoms of many patients with COPD do not satisfactorily improve by using a single, either LABA or LAMA bronchodilator, the synergism of action resulting from the combination of the different bronchodilating mechanisms activated by LABA and LAMA, respectively, can significantly contribute to a better disease control. Based on these clinical and pharmacological considerations, several LABA/LAMA fixed-dose combinations have been developed and experimentally evaluated. Within such a context, the drug co-formulation containing indacaterol and glycopyrronium is probably the LABA/LAMA association which has been most extensively studied during the last few years.

Keywords: Co-formulation; Dual bronchodilation; Glycopyrronium; Indacaterol; LABA; LAMA; QVA149; Synergism.

Figure 1

Dual bronchodilation induced by the fixed-dose co-formulation of indacaterol/glycopyrronium. Indacaterol induces a long-lasting relaxation of airway smooth muscle via a prolonged activation of β₂-adrenergic receptors, coupled through a stimulatory G protein (consisting of α_s, β and γ subunits) to adenylyl cyclase, which catalyzes the synthesis of the intracellular second messenger cAMP. The bronchodilation induced by indacaterol is greatly enhanced by glycopyrronium, which provides a prolonged competitive blockade of M₃ muscarinic receptors. Indeed, glycopyrronium dissociates very slowly from these receptors, whereas it quickly detaches from M₂ receptors. Although the latter may partially contribute to bronchoconstriction via inactivation of adenylyl cyclase mediated by an inhibitory G protein (consisting of α_i, β and γ subunits), they are, however, primarily responsible for pre-junctional inhibition of acetylcholine release.