Montelukast in the treatment of perennial allergic rhinitis in paediatric Japanese patients; an open-label clinical trial

Abstract

Background: This study was conducted to evaluate the safety and tolerability, and population pharmacokinetics (PPK) of montelukast as well as efficacy in the treatment of perennial allergic rhinitis (PAR) in paediatric Japanese patients aged between 1 and 15 years. Methods: In this multi-centre, open-label trial, 87 paediatric Japanese patients with PAR received montelukast 4 mg oral granules (OG) for 4 weeks (1–5-year-olds, N = 15), 4 mg OG for 12 weeks (1–5-year-olds, N = 36), 5 mg chewable tablets (CT) for 12 weeks (6–9-year-olds, N = 18), or 5 mg CT for12 weeks (10–15-year-olds, N = 18). Clinical exams and laboratory assessments were conducted at study visits, and adverse events (AE) were monitored throughout the study up to 14 days after the last visit. Population pharmacokinetic approach was used to estimate AUC0–∞, Cmax, Tmax and apparent elimination half-life in each age group. Efficacy was assessed based on global evaluations by the subject’s caregiver. Results: There were no serious AEs and one discontinuation due to an AE. The most common AEs in any of the treatment groups were nasopharyngitis, pharyngitis, and acute sinusitis. Montelukast exposure (AUC0–∞) was similar in the 1–5-year-old group and the 6–9-year-old group, but 19% lower in the 10–15-year-old group. Among all patients, the total proportion of patients whose global evaluation was “very much better” was 5.7% (week 2), 11.5% (week 4), and 16.9% (week 12) reflecting improvement in symptoms over time. Conclusion: Montelukast was generally well tolerated in Japanese children with PAR. AUC0–∞was similar in 1–5 and 6–9-year-olds, while a lower exposure was observed in the 10–15-year-old group likely due to differences in bodyweight. The exposure in Japanese paediatric patients was generally consistent with that in non-Japanese paediatric and adult patients. As assessed by the patients’ caregivers, montelukast also demonstrated symptomatic improvement based on global evaluations of PAR.

Development and Verification of a Japanese Pediatric Physiologically Based Pharmacokinetic Model with Emphasis on Drugs Eliminated by Cytochrome P450 or Renal Excretion

“…Open and closed symbols are predicted and observed values, respectively. Plasma concentration–time profiles for the CYP2C8 substrate montelukast: (c) 4 mg , 1‐5 years; (d) 5 mg, 6‐9 years; and (e) 5 mg, 10 ‐15 years 51 . Solid black lines are mean values and light‐gray lines are the 5th and 95th percentiles for the predictions.…”

“…The collected data were a mixture of data from IV and oral studies; for oral studies the default absorption parameters have been applied but the finer determinants of absorption have not been considered, for example, granule versus tablet formulation for montelukast. 51 Many of the pediatric studies present data over a very large age range, for example, from 1 month to 18 years, rather than in discrete age bands, which make the data less useful, especially in relation to verification of the underlying ontogeny associated with the elimination pathways. In agreement with a recent study, 16 there were few data presented in neonates; this is a population where further clinical data, including patient information as well as research and verification of the PBPK modeling approach, is needed.…”

“…Some studies had a low “N” number that may not reflect population mean values or variability, but within the simulator it is possible to run many small trials to see how many capture the observed data. The collected data were a mixture of data from IV and oral studies; for oral studies the default absorption parameters have been applied but the finer determinants of absorption have not been considered, for example, granule versus tablet formulation for montelukast 51 . Many of the pediatric studies present data over a very large age range, for example, from 1 month to 18 years, rather than in discrete age bands, which make the data less useful, especially in relation to verification of the underlying ontogeny associated with the elimination pathways.…”

Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial

“…Therefore, montelukast, a leukotriene antagonist and a non-invasive, well-tolerated orally administered drug, represents a promising alternative treatment to CPAP for children with SDB. The efficacy and anti-inflammatory properties of montelukast have been shown in the treatment of several paediatric respiratory conditions, including asthma [ 50 ], exercise-induced bronchospasm [ 51 , 52 ], and allergic rhinitis [ 37 , 53 , 54 ]. Double-blind RCTs have also demonstrated the efficacy of montelukast compared to placebo in non-SCD paediatric patients with SDB and asthma [ 55 – 58 ], even in children as young as 2 years [ 59 ], but these studies have not included cognitive outcomes.…”