Nedocromil Sodium

Summary

Synopsis

Nedocromil sodium¹ is a sodium cromoglycate-like drug which inhibits activation and mediator release from inflammatory cells such as eosinophils, neutrophils, macrophages, monocytes, mast cells and platelets. Non-comparative and placebo-controlled therapeutic studies in adult patients of up to 52 weeks duration have demonstrated the tolerability and efficacy of nedocromil 4mg twice or 4 times daily in the management of reversible obstructive airways disease producing significant improvements in asthma symptom scores and pulmonary function tests. When added to existing therapy, nedocromil sodium permits reductions of 20 to 70% in concomitant bronchodilator use and appears to have a moderate steroid sparing effect in patients receiving inhaled corticosteroids.

To date no controlled studies have been published comparing nedocromil sodium with sodium cromoglycate and other established therapies in adult reversible obstructive airways disease or asthma, which limits the overall conclusions which can be drawn about the position of nedocromil sodium relative to other treatments. However, preliminary clinical data suggest that although nedocromil sodium cannot substitute completely for broncho-dilators or inhaled corticosteroids, with its additive and dose-sparing effects and the convenience of a twice daily dosage it is a promising prophylactic adjunctive agent for the management of reversible obstructive airways disease.

Pharmacodynamic Studies

Nedocromil sodium inhibited activation of, and mediator release from, inflammatory cells such as eosinophils, neutrophils, macrophages, monocytes, mast cells and platelets. It produced in vitro inhibition of histamine, leukotriene C₄ and prostaglandin D₂ release from mucosal mast cells lavaged from the lungs of monkeys sensitised with the nematode Ascaris suum challenged with Ascaris suum antigen or anti-human immunoglobulin E, with a potency at least 100 times greater than sodium cromoglycate (cromolyn sodium). In the Ascaris-sensitive monkey (a model of reversible airways disease) nedocromil sodium was more potent than sodium cromoglycate in preventing bronchoconstriction induced by antigen challenge.

Nedocromil sodium was superior to sodium cromoglycate in reversing bronchoconstriction induced by bradykinin in man. The mechanism of nedocromil sodium’s antiasthmatic action may in part be related to inhibition of axon reflexes, since bradykinin produces axon reflexes releasing sensory neuropeptides.

In bronchial challenge tests in asthmatic volunteers nedocromil sodium was more effective than placebo in inhibiting the immediate bronchoconstrictor response produced by challenge with antigen, adenosine, exercise, sulphur dioxide, cold air and fog. In comparison with sodium cromoglycate, nedocromil sodium was the more effective drug in minimising bronchoconstriction induced by adenosine, sulphur dioxide and cold air challenge but the 2 drugs were equivalent against antigen and exercise challenges.

Pharmacokinetic Studies

Inhalation of nedocromil sodium 4mg produced mean maximum plasma concentrations of 3.3 µg/L. The terminal half-life is equivalent to the absorption half-life at 2.3 hours with absorption from the lungs being rate limiting. Bioavailability is 6 to 9% after inhalation, 2.5% of this being contributed by gastrointestinal absorption. Nedocromil sodium is not metabolised and there is no evidence of accumulation. Following intravenous administration plasma clearance of nedocromil sodium is rapid at 10.2 ml/min/kg via excretion in urine and bile. The pharmacokinetic profile of nedocromil sodium in patients with reversible obstructive airways disease is similar to that observed in healthy volunteers.

Therapeutic Trials

To date no controlled trials have been published comparing nedocromil sodium with sodium cromoglycate or other established therapies. However, non-comparative and placebo-controlled studies of between 4 and 52 weeks duration have demonstrated the tolerability and efficacy of inhaled nedocromil sodium 4mg twice or 4 times daily in adults with all types of reversible obstructive airways disease. Nedocromil sodium has produced improvements in peak expiratory flow rate recorded by patients, symptom scores and use of other medication recorded on diary cards, patient and physician assessments and lung function tests performed at clinic visits.

In placebo-controlled studies, where patients were maintained on bronchodilator therapy, nedocromil sodium produced significant reductions varying from 20 to 70% from baseline in concomitant day and night-time bronchodilator use compared to placebo. In similar controlled studies nedocromil sodium was not able to totally substitute for corticosteroid therapy but enabled maintenance corticosteroid doses to be reduced by 50% or more without loss of symptomatic control in many patients. In some of these studies there were significant improvements, in excess of those produced by the original bronchodilator and/or corticosteroid therapy, with nedocromil sodium compared to placebo. Preliminary studies also suggest nedocromil sodium 4mg twice daily reduces bronchial hyperreactivity occurring through antigen exposure during the pollen season.

Side Effects

The side effects most frequently associated with inhaled nedocromil sodium are distinctive taste (13.6%), headache (4.8%), nausea (4%), vomiting (1.8%), and dizziness (1.2%). Side effects have normally been mild and transient; only 3% of patients admitted to trials, compared to 1.7% for placebo, have withdrawn from therapy as a result of side effects.

Dosage and Administration

The recommended inhaled dose of nedocromil sodium in adults and children over 12 years is 4mg twice daily, increasing to 4 times daily if necessary. Nedocromil sodium is recommended for regular maintenance use and not for relief of symptoms in an acute attack of asthma.