Milgrom H, Skoner DP, Bensch G, Kim KT, Claus R, Baumgartner RA. J Allergy Clin Immunol. 2001;108:938–945
Purpose of the Study.
Racemic albuterol (RAC) consists of equal parts of (R-) and (S)-albuterol, with all the therapeutic activity being found in levalbuterol (LEV), the (R)-isomer. In addition to lacking bronchodilating activity, (S)-albuterol might have properties, suggested by in vitro studies, that might exacerbate airway reactivity and impair asthma control. The authors sought to determine if LEV results in improved safety and efficacy in children.
Children 4 to 11 years old with asthma severity ranging from mild intermittent to moderate persistent were included if baseline forced expiratory volume in 1 second (FEV1) was between 40% and 85% of predicted with at least 15% reversibility to RAC at screening.
Children in this multicenter, randomized, double-blind study received 21 days of LEV (0.31 or 0.63 mg), RAC (1.25 or 2.5 mg), or placebo 3 times daily. Ventolin (GlaxoSmithKline, Research Triangle Park, NC) metered-dose inhalers (MDI) and Nebules (GlaxoSmithKline, Research Triangle Park, NC) were available as rescue medications. The primary endpoint was peak percent change in FEV1 after receiving study medication on day 21. Diary cards were kept, and the Pediatric Asthma Caregiver’s Quality of Life (QOL) Questionnaire was administered at days 0 and 21. Adverse events (AEs), serum potassium and glucose, vital signs, and electrocardiograms were monitored.
All 4 active treatments significantly improved the primary endpoint versus placebo (P < .001), with FEV1 immediately after nebulization as follows: placebo, 2.0%; LEV 0.31 mg, 19%; LEV 0.63 mg, 18.1%; RAC 1.25 mg, 12.4%; and RAC 2.5 mg, 15.6%. Both LEV doses led to significantly greater improvement in FEV1 versus RAC 1.25 mg (P < .05). LEV 0.31 mg was the only treatment not significantly different from placebo for changes in heart rate, QTc interval, and glucose. All active treatments decreased serum potassium. There was no evidence of desensitization to either LEV or RAC as measured by FEV1 at day 21 vs day 0. No significant differences were observed among the treatment groups for diary card parameters or QOL. (S)-albuterol did not appear to affect the clearance of (R)-albuterol. In a subset of patients with severe asthma, a dose-response relationship was observed for LEV, indicating that higher doses were more effective.
LEV had bronchodilator activity comparable to 4- to 8-fold higher doses of RAC and also demonstrated a slightly better safety profile. LEV should be used as the starting dose in 4- to 11-year-old children with asthma. Patients with more severe asthma might benefit from higher doses.
The more favorable therapeutic index for LEV is certainly a valuable feature in children with overtly poor tolerance of RAC and deserves a trial in any child with more severe disease, where response to RAC is suboptimal. There is some suggestion that LEV would be more cost-effective in the hospital setting if it allows for less frequent dosing, as has been claimed. Factors mitigating against the empiric use of LEV first-line, especially at home, include the following: most children overtly tolerate RAC well; AEs noted are generally benign; no MDI form of LEV currently exists; there is a short storage time once a package is opened; and LEV costs much more.