Comparison of the Relative Efficacy of Formoterol and Salmeterol in Asthmatic Patients

Abstract

Studies performed on airway smooth muscle in vitro have indicated that salmeterol is a partial agonist on the beta2-receptor in comparison to formoterol. In the present study we evaluated whether these pharmacological differences between salmeterol and formoterol also are applicable to asthmatic patients. The protective effects by increasing cumulative doses of formoterol (12, 60, 120 micrograms) and salmeterol (50, 250, 500 micrograms) on methacholine-induced bronchoconstriction were evaluated in a double-blind, crossover, placebo-controlled design. Patients were regularly treated with salbutamol 200 micrograms twice daily during the study period, to avoid variability in beta2-adrenoceptor tolerance. S-potassium, heart rate corrected Q-T interval (Q-Tc), and tremor score were followed as measures of systemic effects. Formoterol dose-dependently protected against methacholine responsiveness (4.6 doubling doses after 120 micrograms). Salmeterol, however, showed a flatter dose-response curve, and a significantly weaker maximal protective effect (2.8 doubling doses after 250 micrograms). Formoterol caused a significantly higher tremor score and a larger drop in S-potassium than salmeterol at the highest doses. These data show that salmeterol is a partial agonist on the beta2-receptor in relation to formoterol in human airways in vivo. Further studies are required to document the clinical consequences of this finding, for example in severe asthmatic patients.

Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India

“…In addition, not all patients enrolled in the NJH study exhibited a clear dose-dependent decrease in the eNO levels (data not shown). Similar results were observed for approved doses of SX (50 mcg salmeterol for DPIs and 42 mcg salmeterol f o r p M D I s ) , u s i n g e i t h e r b r o n c h o d i l a t a t i o n o r bronchoprovocation PD model [20,21]. As a result, for the inhalation product containing an ICS and/or a LABA, a CE study should be used to support bioequivalence as part of the weight-of-evidence approach.…”

Budesonide/formoterol for maintenance and reliever therapy in the management of moderate to severe asthma

“…The rapid and sustained effects of formoterol on bronchodilation/bronchoprotection are well documented and have been mentioned earlier in this review (39,40). Other positive effects reported with LABAs include a reduction in the airway oedema that can occur during an asthma exacerbation by relaxing the endothelial cells (72), inhibition of the release of bronchoconstrictors, such as histamines, from mast cells (73) and beneficial effects on neutrophilic inflammation (23) (Fig.…”

“…The onset of action is not sufficient to provide immediate relief. Moreover, the partial agonist properties limit the benefit of increasing the dose above 100 lg/day (39,41). In a study involving a methacholine challenge, increasing the dose of salmeterol did not lead to enhanced bronchoprotection, in contrast to the added protection observed with increased doses of formoterol (39).…”

“…Corticosteroids can also prevent the tolerance that can occur in response to prolonged administration of b 2 -agonists (62) and reverse the uncoupling of b 2 -receptors that occurs subsequent to b 2 -agonist administration (63). In smooth muscle, the dose-related bronchoprotection provided by formoterol compared with salmeterol may be an important added benefit of this LABA (39), particularly during an exacerbation where there is an increase in airway tone caused by cytokine-mediated bronchoconstriction. In addition, the benefits of a stronger agonist on inflammatory cells such as mast cells and neutrophils which have few functioning receptors may also be important (23,64) (Fig.…”

Beta-2 agonist discussions in asthma and a review of current data

“…In clinical practice, however, there is no evidence suggesting that formoterol is more effective than salmeterol. A randomized double blind study performed in patients with asthma has shown that high dose formoterol provided better protection against metacholine-induced bronchoconstriction compared to salmeterol (20,21).…”