Adaptive clinical trial with pharmacokinetic-guided optimization of weight-based oral montelukast dose in children with acute asthma exacerbations

Donald H. Arnold; Leonard B. Bacharier; James C. Slaughter; Theodore Reiss; Ashley Houser; James W. Antoon; Maria C. Balanta; Wendell S. Akers

doi:10.18203/2349-3259.ijct20263758

Authors

Donald H. Arnold Department of Pediatrics, Vanderbilt University School of Medicine, Children’s Way, Nashville, TN, USA
Leonard B. Bacharier Department of Pediatrics, Vanderbilt University School of Medicine, Children’s Way, Nashville, TN, USA
James C. Slaughter Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA
Theodore Reiss New Hope, PA, USA
Ashley Houser
James W. Antoon Department of Pediatrics, Vanderbilt University School of Medicine, Children’s Way, Nashville, TN, USA
Maria C. Balanta Department of Pediatrics, Vanderbilt University School of Medicine, Children’s Way, Nashville, TN, USA
Wendell S. Akers Department of Pharmaceutical Sciences, Lipscomb University, Nashville, TN, USA

DOI:

https://doi.org/10.18203/2349-3259.ijct20263758

Keywords:

Anti-asthmatic agents, Asthma, Glucocorticoids, Leukotriene E4, Leukotriene antagonist, Montelukast, Status asthmaticus

Abstract

Background: Children with acute asthma exacerbations are frequently hospitalized due to insufficient response to inhaled β-agonist and systemic corticosteroid treatments. Leukotriene (LT) mediated airway inflammation does not respond to these medications and contributes to insufficient clinical response that often necessitates hospitalization. Montelukast (MK) is a potent LT receptor antagonist, and IV MK caused rapid clinical improvement in adults with exacerbations, though the IV form is not FDA approved or currently available.

Methods: This is a phase 2, adaptive, double-masked RCT of high-dose oral MK, with escalating mg/kg dose levels informed by PK-guided modeling, added to standard treatment versus standard treatment alone, in children with exacerbations that are moderate or severe after initial treatment with inhaled albuterol. Study hypotheses are that-High-dose oral MK achieves peak plasma levels (C_max)>1,700 ng/ml in >86% of at least one of three sequential participant groups with escalating weight-based (mg/kg) doses between groups; participants randomized to high-dose oral MK have a 2 point or greater improvement of the validated acute asthma intensity research score (AAIRS) at 4 hours post-treatment in comparison with control group participants; and among MK recipients, C_max correlates with change of the AAIRS at 4 hours, after adjustment for pre-treatment exacerbation severity, respiratory viral detection, and systemic LT stress measured using plasma LTE₄.

Conclusions: This research will provide critical data for dosing and design decisions for a future randomized trial sufficiently powered to definitively determine efficacy in this population.

Trial Registration: NCT 05819541.

References

Bourgeois FT, Monuteaux MC, Stack AM, Neuman MI. Variation in emergency department admission rates in US children's hospitals. Pediatrics. 2014;134(3):539-45.

Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013;131(3):636-45.

Boardman C, Chachi L, Gavrila A, Keenan CR, Perry MM, Xia YC, et al. Mechanisms of glucocorticoid action and insensitivity in airways disease. Pulmonary Pharmacol Therapeut. 2014;29(2):129-43.

Altman MC, Gill MA, Whalen E, Babineau DC, Shao B, Liu AH, et al. Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children. Nat Immunol. 2019;20(5):637-51.

Arnold DH. Acute asthma exacerbations, viral respiratory infections, and corticosteroid treatment. Lancet Respir Med. 2016;4(12):930-2.

Lazarinis N, Bood J, Gomez C, Kolmert J, Lantz AS, Gyllfors P, et al. Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor. J Allergy Clin Immunol. 2018;142(4):1080-9.

Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Eng J Med. 1999;340(3):197-206.

McCarthy MK, Weinberg JB. Eicosanoids and respiratory viral infection: coordinators of inflammation and potential therapeutic targets. Mediators Inflammation. 2012;2012:236345.

Green SA, Malice MP, Tanaka W, Tozzi CA, Reiss TF. Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation. Thorax. 2004;59(2):100-4.

Reiss TF, Hill JB, Harman E, Zhang J, Tanaka WK, Bronsky E, et al. Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax. 1997;52(12):1030-5.

Baraldi E, Ghiro L, Piovan V, Carraro S, Ciabattoni G, Barnes PJ, Montuschi P. Increased exhaled 8-isoprostane in childhood asthma. Chest. 2003;124(1):25-31.

Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010;125(2-2):S73-80.

Ono E, Mita H, Taniguchi M, Higashi N, Tsuburai T, Hasegawa M, et al. Increase in inflammatory mediator concentrations in exhaled breath condensate after allergen inhalation. J Allergy Clin Immunol. 2008;122(4):768-73.e1.

Sebaldt RJ, Sheller JR, Oates JA, Roberts LJ, 2nd, FitzGerald GA. Inhibition of eicosanoid biosynthesis by glucocorticoids in humans. Proceedings National Academy Sci U. S Am. 1990;87(18):6974-8.

Dworski R. Oxidant stress in asthma. Thorax. 2000;55(2):S51-3.

Negri J, Early SB, Steinke JW, Borish L. Corticosteroids as inhibitors of cysteinyl leukotriene metabolic and signaling pathways. J Allergy Clin Immunol. 2008;121(5):1232-7.

Merck Co, Inc. Singulair Highlights of prescribing information. 2019. Available from: https://www.merck.com/product/usa/pi_circulars/s/singulair/singulair_pi.pdf. Accessed on 22 July 2026.

Reiss TF, Altman LC, Chervinsky P, Bewtra A, Stricker WE, Noonan GP, et al. Effects of montelukast (MK-0476), a new potent cysteinyl leukotriene (LTD4) receptor antagonist, in patients with chronic asthma. J Allergy Clin Immunol. 1996;98(3):528-34.

Reiss TF, Sorkness CA, Stricker W, Botto A, Busse WW, Kundu S, et al. Effects of montelukast (MK-0476); a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled corticosteroids. Thorax. 1997;52(1):45-8.

Camargo CA Jr, Smithline HA, Malice MP, Green SA, Reiss TF. A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respiratory Crit Care Med. 2003;167(4):528-33.

Camargo CA Jr, Gurner DM, Smithline HA, Chapela R, Fabbri LM, Green SA, et al. A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma. J Allergy Clin Immunol. 2010;125(2):374-80.

Arnold DH, Van Driest SL, Reiss TF, King JC, Akers WS. Pilot Study of Peak Plasma Concentration After High-Dose Oral Montelukast in Children With Acute Asthma Exacerbations. J Clin Pharmacol. 2021;61(3):360-7.

Cheng H, Leff JA, Amin R, Gertz BJ, De Smet M, Noonan N, et al. Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females. Pharmaceut Res. 1996;13(3):445-8.

Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health. National Heart, Lung, and Blood Institute; 2007. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/01_front.pdf. Accessed on 22 July 2026.

Global strategy for asthma management and prevention, 2024. Global Initiative for Asthma. 2024. Available at: https://ginasthma.org/2024-report/. Accessed on 22 July 2026.

Arnold DH, Saville BR, Wang W, Hartert TV. Performance of the Acute Asthma Intensity Research Score (AAIRS) for acute asthma research protocols. Ann Allergy Asthma Immunol. 2012;109(1):78-9.

Behrens B, Swetlitz C, Pine DS, Pagliaccio D. The Screen for Child Anxiety Related Emotional Disorders (SCARED): Informant Discrepancy, Measurement Invariance, and Test-Retest Reliability. Child Psychiatry Hum Dev. 2019;50(3):473-82.

Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-77.

FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis: U.S. Food and Drug Administration; 2020. Available at: https://www.fda.gov/media/135840/download. Accessed on 22 July 2026.

About the Food and Drug Administration (FDA) Sentinel Initiative 2026. Description of the FDA Sentinel Initiative and the Sentinel Distributed Database]. Available at: https://www.sentinelinitiative.org/about. Accessed on 22 July 2026.

Sansing-Foster V, Haug N, Mosholder A, Cocoros NM, Bradley M, Ma Y, et al. Risk of Psychiatric Adverse Events Among Montelukast Users. J Allergy Clin Immunol Practice. 2021;9(1):385-93.e12.

Wintzell V, Brenner P, Halldner L, Rhedin S, Gong T, Almqvist C. Montelukast Use and the Risk of Neuropsychiatric Adverse Events in Children. JAMA Pediatr. 2025;179(4):418-27.

Arnold DH, Bowman N, Reiss TF, Hartert TV, Seger DL. Adverse events are rare after single-dose montelukast exposures in children. Clin Toxicol. 2018;56(1):25-9.

Bisgaard H, Skoner D, Boza ML, Tozzi CA, Newcomb K, Reiss TF, et al. Safety and tolerability of montelukast in placebo-controlled pediatric studies and their open-label extensions. Pediatr Pulmonol. 2009;44(6):568-79.

R Core Team. R: A language and Environment for Statistical Computing. Vienna, Austria. Available at: http://www.r-project.org/2024. Accessed on 22 July 2026.

Gern JE. Viral respiratory infection and the link to asthma. Pediat Infect Dis J. 2008;27(10):S97-103.

Navanandan N, Thompson T, Pyle L, Florin TA. Defining Treatment Response for Clinical Trials of Pediatric Acute Asthma. J Allergy Clin Immunol Pract. 2023;11(5):1450-8.e1.

Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 Explanation and Elaboration: Updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010;63(8):e1-37.

Chan AW, Boutron I, Hopewell S, Moher D, Schulz KF, Collins GS, et al. SPIRIT 2025 statement: updated guideline for protocols of randomised trials. Lancet. 2025;405(10491):e19-27.