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By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The pharmaceutical company sepracor has created a unique niche for itself by focusing on developing Improved Chemical Entities (ICEs), single-isomer or active-metabolite versions of currently marketed drugs. Their objective is to develop new versions of popular drugs with improved side effect profiles, onset of action, or duration of action by purification of racemic mixtures.
They have had development deals with other manufacturers, but the company’s first individual entry in the market is levalbuterol (Xopenex) for the treatment or prevention of bronchospasm. Levalbuterol is the active (R)-isomer of racemic albuterol. The R-isomer is the active bronchodilating component of racemic albuterol and is touted as offering comparable bronchodilation to racemic albuterol with fewer side effects. The drug is only available as liquid for use in nebulizers.
Levalbuterol is indicated for the treatment or prevention of bronchospasm in adults and adolescents 12 years of age and older with reversible obstructive airway disease.
The usual starting dose is 0.63 mg administered by nebulization three times a day, every 6-8 hours. Patients with more severe asthma or who do not respond adequately to a dose of 0.63 mg may increase the dose to 1.25 mg three times a day.1
Levalbuterol is supplied as a preservative-free 3 mL unit-dose of 0.63 mg and 1.25 mg.
In vitro data indicate that levalbuterol has a greater affinity for the beta-adrenergic receptors than racemic albuterol and has 100 greater affinity than the (S)-isomer.1,2 The S-isomer of racemic albuterol has been associated with some bronchoconstrictive reponse to methacholine with chronic use.3 In a four-week comparative trial of racemic albuterol and levalbuterol (n = 362), levalbuterol produced a numerically better (0.84-0.74 L) but not statistically different improvement in FEV1 (forced expiratory volume in one second). Levalbuterol at 0.63 mg was comparable to 2.5 mg of albuterol—levalbuterol 1.25 mg being the most potent and albuterol 1.25 mg the least potent.4 Similar findings were reported in a crossover study in pediatric patients.5 In the clinical trial of equipotent doses (0.63 mg of levalbuterol and 2.5 mg of albuterol), levalbuterol caused a lower incidence of nervousness at four weeks (2.8% vs 8.1%) and first-dose increase in heart rate (2.4% vs 5.7%).1
Levalbuterol is available only as a solution for neubulization—not as the more commonly used and convenient metered-dose inhaler or dry powder for inhalation.
Many of the drugs are marketed as racemic mixture. Due to the presence of at least one asymmetric center, these mixtures generally comprise a more active isomer (eutomer) and a less active isomer (distomer). The differences in activity result from stereoselective binding of the drug to various macromolecules (e.g., receptors, enzymes). The distomers can vary in their contribution to the pharmacologic effects of the racemic mixture, and these can range from lack of any activity to antagonism, toxicity, or even completely different activity. The example of the latter is quinine and quinidine. In the case of levalbuterol, limited data suggest that the distomer (S-isomer) may have some antagonistic effect on pulmonary function. Results from clinical data indicate that levalbuterol 0.63 mg is comparable to albuterol 2.5 mg, and levalbuterol 1.25 mg produces the greatest improvement in FEV1.4 These results seem to be consistent with the possible antagonistic effect of the distomer.
The average wholesale cost of levalbuterol is $1.98 per unit-dose vial, which is 10-15% higher than branded albuterol (Proventil or Ventolin) and is more expensive than generic albuterol ($1.21 per unit-dose vial).
In theory, it appears that levalbuterol may offer some clinical advantage over racemic albuterol; however, in a large clinical trial involving more than 360 patients, the improvement in FEV1 was not statistically significant after four weeks. Equipotent doses of levalbuterol and albuterol showed a small difference in favor of levalbuterol for certain beta-adrenergic mediated adverse effects. Therefore, the clinical advantage of administering the pure eutomer over the racemic mixture has not been clearly established.
1. Xopenex Product Information. Sepracor. March 1999.
2. Perrin-Fayolle M. Lancet 1995;346:1101.
3. The Medical Letter 1999;41:51-52.
4. Nelson HS, et al. J Allergy Clin Immunol 1998;102(6 Pt 1):943-952.
5. Gawchik SM, et al. J Allergy Clin Immunol 1999; 103(4):615-621.