Montelukast in the Treatment of Duodenal Eosinophilia in Children With Dyspepsia: Effect on Eosinophil Density and Activation in Relation to Pharmacokinetics

I. Background/Rationale

Recurrent abdominal pain is a common complaint among school-age children, being present in up to 15% at any given time. It represents the most common chronic pain entity in pediatric patients. These patients frequently have dyspepsia defined as upper abdominal pain or discomfort. (1) Eighty-three percent of children referred to our institution for recurrent pain have dyspepsia. Shaffer, et al, found dyspepsia to be present in 73% of 154 children with recurrent abdominal pain. (2)

We have found mucosal eosinophilia in 71% of children undergoing endoscopy with mucosal biopsy for dyspepsia. However, eosinophil density does not necessarily correlate with eosinophil activation and many eosinophil-derived mediators are bioactive in a concentration-dependent fashion. (3) In previous investigations, we have found evidence of moderate to extensive eosinophil degranulation in the biopsies of dyspeptic children who had normal mucosal eosinophil densities. (4)

Montelukast is a competitive antagonist of the cys LT1 receptor with an affinity that is similar, but lower than that of leukotriene D4. (5) We and others have previously reported good clinical response to montelukast in patients with eosinophilic gastroenteritis. (6-9) Recently, Vanderhoof and Young (8) reported eight patients with dysphagia, diarrhea, and/or constipation associated with tissue eosinophilia who had prolonged remission of symptoms with montelukast therapy. This experience prompted us to undertake a double-blinded placebo-controlled cross-over trial of montelukast in dyspeptic children with duodenal eosinophilia. We were able to demonstrate the superiority of montelukast as compared to placebo in the relief of pain. (9) Despite an average duration of pain of nearly 22 months prior to study enrollment, approximately one-half of the patients became pain free or nearly pain-free during the two week course of therapy with montelukast. Also of interest from this particular study was the finding that montelukast pharmacokinetics, and thus exposure, were different than previously observed in children receiving the drug. Specifically, the average population elimination t-1/2 for montelukast in our subjects (1.8 hours) was substantially shorter than mean values for this parameter (3.4 hours) determined from children without concurrent intestinal disease. (5, 10) While the reasons for this apparent disparity are not clear, it is possible that local montelukast metabolism (ie., in the small intestine) may vary as a consequence of disease state. Nonetheless, what remains to be determined is whether there is a link between systemic and tissue levels and whether an exposure-response relation can be established for montelukast in pediatric patients with eosinophilic duodenitis.

Finally, the mechanism responsible for the demonstrated clinical efficacy of montelukast in this disorder has not been established. It is possible that the therapeutic effect might result consequent to a lowering in eosinophil density, alteration of the eosinophil activation state, blocking leukotrienes released by eosinophils (or other cells) at their site of action, or any combination of the aforementioned effects. The clinical effectiveness of medications for eosinophilic esophagitis has been previously found to be associated with a decrease in eosinophil density, but the activation state was not assessed. (11-12) As well, no previous investigations of therapeutic interventions for this disorder have addressed exposure-response relationships.