Pharmacokinetic-guided optimization of weight-based dosing for high-dose oral montelukast in children with acute asthma exacerbations

<jats:p>&lt;b&gt;Background and Purpose&lt;/b&gt;: Children with acute asthma exacerbations are frequently hospitalized due to insufficient response to inhaled β-agonist and systemic corticosteroid potentially due to leukotriene mediated airway inflammation. Montelukast is a potent leukotriene receptor antagonist approved for chronic asthma treatment. We performed a randomized dose-escalation trial of high-dose oral montelukast to identify the dose of oral montelukast suitable for future efficacy studies. &lt;b&gt;Experimental Approach:&lt;/b&gt; We performed a Phase 2, adaptive, double-masked randomized controlled trial comparing high-dose oral montelukast plus standard treatment versus standard alone in children with exacerbations moderate-to-severe exacerbations after initial inhaled albuterol treatment. Three sequential groups received escalating weight-based dose levels (2.0, 2.5, and 3.0 mg/kg) with maximum plasma concentration (Cmax) used as the pharmacokinetic target for dose escalation. We hypothesized that at least one dose level would achieve a target Cmax of 1,700 ng/ml in &lt;u&gt;&gt;&lt;/u&gt; 86% of dose-level participants. &lt;b&gt;Key Results:&lt;/b&gt; Among 45 participants randomized to montelukast and 44 to placebo, median [IQR] ages were 6.6 [5.4, 10] and 6.7 [5.3, 9.9] years, with high-moderate pre-treatment exacerbation severity. The target Cmax was reached in 67%, 80%, and 90% of participants at doses of 2.0, 2.5, and 3.0 mg/kg, respectively. Adverse events were infrequent and mild. &lt;b&gt;Conclusion and Implications:&lt;/b&gt; Among children with moderate or severe acute asthma exacerbations not responsive to initial inhaled albuterol, oral montelukast at a dose of 3.0 mg/kg reliably achieves a potentially therapeutic Cmax. These findings support dose selection for an adequately powered efficacy trial of montelukast in this population.</jats:p>