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Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy

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Abstract

Background

A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols.

Objectives and Methods

The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated.

Results

A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment.

Conclusions

This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

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Acknowledgments

The authors thank the patients and the parents of pediatric patients who participated in this study. The authors also thank Unité de Recherche Clinique Centre d’Investigation Clinique Paris Descartes Necker-Cochin (URC-CIC Paris Necker/Cochin; Victor BRUYERE) for data management of the study. The authors also thank Céline Hauw, Céline Awotar, Déborah Richard, Diane Achimatos, Mélanie Vassal, Anais Beulaygue, Julie Le Gall, Amina Ziouche, Mahamadi Savagodo, Alexandre Coudrat, Amélie Arrouy, Alix Laurent, Maud Guillet, Myriam Aubry, Emilie Wald Cécile Valentin, and Catherine Bellot for implementation of the study. The authors also thank Dr. Mélissandre Baravalle, Dr. Katia Bessaci, Dr. Laure Couderc, Dr. Caroline Faucon, Dr. Asma Gabsi, Dr. Marie-Christine Werck-Gallois, Dr. Michèle Gérardin, Dr. Géraldine Labouret, Dr. Muriel Laurans, Dr. Sophie L'Excellent, Dr. Marie Mittaine, Dr. Camille Ohlmann, Dr. Natascha Remus, and Dr. Emeline Roy for enrolment of patients.

Author information

Authors and Affiliations

  1. Université Paris Cité, EA7323, Paris, France

    Naïm Bouazza, Saïk Urien, Frantz Foissac, Gabrielle Lui, Léo Froelicher Bournaud, Romain Berthaud, Michaela Semeraro, Jean-Marc Treluyer & Sihem Benaboud

  2. Unité de Recherche Clinique Necker Cochin, AP-HP, Paris, France

    Naïm Bouazza, Saïk Urien, Frantz Foissac, Laure Choupeaux, Jean-Marc Treluyer & Sihem Benaboud

  3. CIC-1419 Inserm, Cochin-Necker, Paris, France

    Naïm Bouazza, Saïk Urien, Frantz Foissac, Romain Berthaud, Michaela Semeraro & Jean-Marc Treluyer

  4. Service de Pharmacologie Clinique, Hôpital Cochin, AP-HP, Groupe Hospitalier Paris Centre, Paris, France

    Gabrielle Lui, Léo Froelicher Bournaud, Steeve Rouillon, Yi Zheng & Sihem Benaboud

  5. INSERM, CNRS, Institut Necker-Enfants Malades, Paris, France

    Emmanuelle Bardin

  6. Département de Biotechnologie de la Santé, Université Paris-Saclay, UVSQ, INSERM U1173, Infection et inflammation, Montigny le Bretonneux, France

    Emmanuelle Bardin

  7. Hôpital Necker Enfants Malades, Centre de Référence Maladies Rares Mucoviscidose et Maladies apparentées, Paris, France

    Emmanuelle Bardin & Isabelle Sermet-Gaudelus

  8. Paediatric Cystic Fibrosis Resources and Competences Centre, Hôpital de la Timone, CHU de Marseille, Marseille, France

    Nathalie Stremler

  9. Mixed Cystic Fibrosis Resources and Competences Centre, Hôpital Américain, Reims, France

    Katia Bessaci

  10. Chronic Childhood Diseases Unit, Pediatric Department, Nantes University Hospital, Nantes, France

    Tiphaine Bihouee

  11. Pediatric Department, CHU Versailles, Le Chesnay, France

    Emmanuelle Coirier-Duet

  12. Centre de Ressources et de Compétences de la Mucoviscidose, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France

    Christophe Marguet

  13. Centre Hospitalier Universitaire de Rennes, Centre de Ressource et de Compétences de la Mucoviscidose, Rennes, France

    Eric Deneuville

  14. Centre de Ressources et de Compétences de la Mucoviscidose, Centre Hospitalier Universitaire de Caen Normandie, Caen, France

    Muriel Laurans

  15. Centre de ressources et de compétences pour la mucoviscidose, Site Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France

    Philippe Reix

  16. Université de Lyon, université Lyon, CNRS, UMR 5558, équipe EMET, 69100, Villeurbanne, France

    Philippe Reix

  17. CF Pediatric Centre, Robert Debré Hospital, AP-HP, 75019, Paris, France

    Michèle Gerardin

  18. Centre de ressources et de compétences pour la mucoviscidose, Hôpital des enfants, CHU Toulouse, Toulouse, France

    Marie Mittaine

  19. Pediatric Department, Centre Hospitalier Intercommunal de Créteil, Créteil, France

    Ralph Epaud

  20. Paediatric Pulmonology and Allergy Unit, Hôpital Jeanne de Flandre, CHU Lille, Université de Lille, 59000, Lille, France

    Caroline Thumerelle

  21. Centre de Ressources et de Compétences de la Mucoviscidose, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    Laurence Weiss

  22. Université Paris-Cité, Paris, France

    Isabelle Sermet-Gaudelus

  23. ERN-Lung CF network, Frankfurt, Germany

    Isabelle Sermet-Gaudelus

Authors
  1. Naïm Bouazza
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  2. Saïk Urien
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  3. Frantz Foissac
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  4. Laure Choupeaux
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  6. Léo Froelicher Bournaud
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  7. Steeve Rouillon
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  8. Yi Zheng
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  9. Emmanuelle Bardin
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  10. Nathalie Stremler
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  11. Katia Bessaci
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  13. Emmanuelle Coirier-Duet
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  14. Christophe Marguet
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  15. Eric Deneuville
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  16. Muriel Laurans
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  17. Philippe Reix
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  18. Michèle Gerardin
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  19. Marie Mittaine
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  20. Ralph Epaud
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  21. Caroline Thumerelle
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  22. Laurence Weiss
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  23. Romain Berthaud
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  24. Michaela Semeraro
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  25. Jean-Marc Treluyer
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  26. Sihem Benaboud
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  27. Isabelle Sermet-Gaudelus
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Corresponding author

Correspondence to Naïm Bouazza.

Ethics declarations

Funding

The study was supported by a grant from the French Ministry of Health (PHRC 2017, PREDICT-CF). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests

The authors have no competing interests to declare in relation to this work.

Ethics approval

This study was approved by the institutional review board (Comité de Protection des Personnes, Nord Ouest IV, no. EUDRACT: 2018-002624-16) and registered in the clinicaltrails.gov database under reference NCT03894657.

Consent to Participate

Written, informed consent was obtained from all participants or their guardians.

Consent for publication

Not applicable.

Data availability statement

Data from this study cannot be shared publicly, as the procedures carried out with the French data privacy authority [Commission nationale de l'informatique et des libertés (CNIL)] do not provide for the transmission of the database, nor do the information and consent documents signed by the patients. Consultation of the data by other interested researchers may be considered by AP-HP, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable French and European regulations. The request must be addressed to the Delegation for Clinical Research and Innovation (DRCI) at secretariat-direction.drc@aphp.fr.

Code availability

Not applicable.

Author contributions

NB, JMT, and ISG contributed to the study conception and design. Material preparation, data collection, and analysis were performed by NB, SU, FF, LC, GL, LFD, SR, YZ, NS, KB, TB, ECD, CM, ED, ML, PR, MG, MM, RE, CT, LW, RB, MS, SB, and ISG. The first draft of the manuscript was written by NB, EB, ISG, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Bouazza, N., Urien, S., Foissac, F. et al. Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy. Clin Pharmacokinet 63, 333–342 (2024). https://doi.org/10.1007/s40262-023-01342-3

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