Pilot Study of Peak Plasma Concentration After High‐Dose Oral Montelukast in Children With Acute Asthma Exacerbations

Abstract

Acute asthma exacerbations are primarily due to airway inflammation and remain one of the most frequent reasons for childhood hospitalizations. Although systemic corticosteroids remain the mainstay of therapy because of their anti‐inflammatory properties, not all inflammatory pathways are responsive to systemic corticosteroids, necessitating hospital admission for further management. Cysteinyl leukotrienes (LTs) are proinflammatory mediators that play an important role in systemic corticosteroids non‐responsiveness. Montelukast is a potent LT‐receptor antagonist, and an intravenous preparation caused rapid, sustained improvement of acute asthma exacerbations in adults. We hypothesized that a 30‐mg dose of oral montelukast achieves peak plasma concentrations (Cmax), comparable to the intravenous preparation (1700 ng/mL) and would be well tolerated in 15 children aged 5 to 12 years with acute asthma exacerbations. After administration of montelukast chewable tablets, blood samples were collected at 0, 15, 30, 45, 60, 120, 180, and 240 minutes. Plasma was separated and frozen at −80°C until analysis for montelukast concentration using liquid chromatography‐ tandem mass spectrometry. Median time to Cmax (tmax) was 3.0 hours. Six participants (40%) achieved Cmax of 1700 ng/mL or higher. However, there was high interindividual variability in peak plasma concentration (median Cmax of 1378 ng/mL; range, 16‐4895 ng/mL). No participant had side effects or adverse events. Plasma concentrations from this pilot study support the design of a weight‐based dose‐finding study aimed at selecting an optimal dose for future clinical trials to assess the efficacy of high‐dose oral montelukast in children with moderate to severe asthma exacerbations.

Role of Leukotriene Antagonists in the Treatment of Asthma Exacerbations

“…Leukotriene is an inflammatory mediator that is produced by eosinophils and mast cells in the respiratory system and leads to inflammatory responses such as bronchospasm by contracting the smooth muscles, bronchial hyperresponsiveness, and increased vascular leakage leading to edema and airway remodeling. Its production can also be boosted by respiratory viruses, especially rhinoviruses, and allergens [7,8].…”

“…Leukotriene antagonists, such as Montelukast, have been used successfully in the treatment of mild persistent asthma as well as moderate asthma as adjuvant therapy or to reduce the ICS dose and side effects related to its long-term use [9,10]. In addition to their effectiveness in managing chronic conditions, they have also been shown to be effective in treating asthma attacks and raising the forced expiratory volume in one second (FEV1) [7].…”