Montelukast Dose Selection in 6‐ to 14‐Year‐Olds: Comparison of Single‐Dose Pharmacokinetics in Children and Adults

Abstract

Montelukast, an oral leukotriene-receptor antagonist, has demonstrated efficacy and tolerability for the treatment of chronic asthma in adults. A once-daily 10 mg dose (film-coated tablet) was selected as the optimal adult dose based on dose-ranging studies. Asthma is a similar disease and is treated with the same medications in children and adults. These observations suggested that a dose of montelukast in children providing overall drug exposure (i.e., montelukast plasma concentrations) similar to that of the 10 mg film-coated tablet dose in adults would be efficacious, well tolerated, and obviate the need for separate dose-ranging studies in children. Therefore, the dose of montelukast for 6- to 14-year-old children was selected by identifying the chewable tablet dose of montelukast yielding a single-dose area under the plasma concentration-time curve (AUC) comparable to that achieved with the adult 10 mg film-coated tablet dose. Based on this approach, which included dose normalization of data from several pediatric pharmacokinetic studies, a 5 mg chewable tablet dose of montelukast was selected for use in clinical efficacy studies in 6- to 14-year-old children with asthma.

A Population Pharmacokinetic Model for Montelukast Disposition in Adults and Children

“…The steady-state volume of distribution and clearance in a 70-kg adult were estimated to be 8.2 L and 43 ml/min, respectively, which is consistent with published results that use traditional noncompartmental analysis (13). Previous studies after oral administration of montelukast have indicated that the pharmacokinetic profiles of montelukast are different in adults and children (23). Consistent with those observations, we observed dissimilar pharmacokinetics after intravenous administration between the two populations that we studied.…”

“…A 10-mg film-coated tablet in adults, a 5-mg chewable tablet in children aged 6 to 14 years, and a 4-mg chewable tablet or oral granules in children aged 2 to 5 years are approved for use in the clinic. These oral doses yield similar systemic exposures that are also associated with efficacy in the respective age groups (15,17,23). In adult patients with chronic asthma, a single 7-mg intravenous dose was found to be as effective as a 10-mg oral dose of montelukast (31).…”

“…Most of the data published include routine noncompartmental analysis. Sparse data from pediatric studies in children aged 6 months to 5 years have been modeled with a one-compartment model (15,16,23); however, the choice of model was empirical, and other models were not explored due to the sparsity of the data collected.…”

“…However, these exposures do not pose a concern with respect to safety, as early clinical studies have shown that intravenous doses up to 18 mg (mean exposure ∼7600 ng·h/ml) have been well tolerated in adults (13). Exposures of 3528 (±1883) ng·h/ ml have been observed in pediatric patients after oral administration of a 10-mg dose of the film-coated tablet formulation of montelukast, and these were well tolerated as well (23). Also, it is known that montelukast has a wide therapeutic index, and no dose-related toxicity has been observed in adult subjects treated with oral doses substantially higher than 10 mg (24).…”

Montelukast Sodium: Administration to Children to Control Intermittent Asthma

“…34 Yet another study indicated that a 5 mg chewable tablet administered once daily to children aged 6-14 years with asthma, resulted in a pharmacokinetic profile comparable to that of the clinically effective 10 mg FCT dose in adults. 35 …”