Proof-of-concept evaluation of trough airway hyper-responsiveness following regular racemic or levosalbutamol in genotype-stratified steroid-treated persistent asthmatic patients

Asthmatic patients receiving ICSs (inhaled corticosteroids) may take frequent add-on therapy with salbutamol despite on-demand prescription. Frequent salbutamol use can be detrimental in asthma. The isomeric formulation of salbutamol and the B2ADR (β₂ adrenoceptor) 16 genotype may also influence this phenomenon. We performed a randomized, double-blind, placebo-controlled, triple crossover, proof of concept trial comparing 2 weeks of regular therapy with inhaled racemic salbutamol [200 μg q.i.d. (four times daily)], levosalbutamol (100 μg q.i.d.) or placebo on trough methacholine PC₂₀ [provocative concentration causing 20% fall in FEV₁ (forced expiratory volume in 1 s)] 6 h post-dose (the primary outcome) in 30 persistent asthmatic patients (15 who were Arg¹⁶ homozygous and 15 who were Gly¹⁶ homozygous) all receiving ICSs. There was no worsening of AHR (airway hyper-responsiveness) at trough to methacholine after 2 weeks regular exposure to either racemic (P=0.53) or levosalbutamol (P=0.84) compared with placebo, nor between genotypes–as dd (doubling dilution) difference in methacholine PC₂₀ from placebo [salbutamol/Arg¹⁶=0.36 dd [95% CI (confidence interval), −0.43, 1.15]; salbutamol/Gly¹⁶=0.01 dd (95% CI, −0.47, 0.49); levosalbutamol/Arg¹⁶=−0.01 dd (95% CI, −0.89, 0.87); and levosalbutamol/Gly¹⁶=0.28 dd (95% CI, −0.22, 0.77)]. Both active treatments improved morning PEF (peak expiratory flow) in Gly¹⁶ (P=0.04 overall) but not Arg¹⁶ (P=0.50 overall) patients, whereas evening PEF improved in both Gly¹⁶ (P<0.001 overall) and Arg¹⁶ (P=0.006 overall) patients. In conclusion, the regular exposure to either racemic or levosalbutamol for 2 weeks added to ICSs did not cause worsening of AHR at trough compared with placebo; with no difference seen between B2ADR 16 genotypes.