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J Cyst Fibros. 2019 May;18(3):368-374. doi: 10.1016/j.jcf.2018.12.011. Epub 2018 Dec 28.

Predictive factors for lumacaftor/ivacaftor clinical response.

Author information

1
Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France; Centre de Référence et de Compétence de la Mucoviscidose, Hôpital Dupuytren, 8 avenue Dominique Larrey, 87042 Limoges, France.
2
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Lung Health Research Center, Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia. Electronic address: elena.schneider@monash.edu.
3
Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France. Electronic address: nesrine.baatallah@inserm.fr.
4
Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France; Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France; Laboratoire de Biochimie Générale, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de Sèvres, 75015 Paris, France. Electronic address: thao.nguyen-khoa@aphp.fr.
5
Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France; Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance-Publique Hôpitaux de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France. Electronic address: emmanuelle.girodon@aphp.fr.
6
Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France. Electronic address: aurelie.hatton@inserm.fr.
7
Centre de Ressources et de Compétence de la Mucoviscidose Adulte, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire, 2 boulevard Tonnellé, 37000 Tours, France. Electronic address: t.flament@chu-tours.fr.
8
Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France. Electronic address: muriel.lebourgeois@aphp.fr.
9
Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France. Electronic address: frederique.chedevergne@aphp.fr.
10
Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France. Electronic address: celine.bailly@aphp.fr.
11
Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France.
12
Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France. Electronic address: diane.achimastos@aphp.fr.
13
Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France. Electronic address: alexandre.hinzpeter@inserm.fr.
14
Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France. Electronic address: aleksander.edelman@inserm.fr.
15
Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France; Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France; Université Paris Sorbonne, 75005 Paris, France. Electronic address: isabelle.sermet@aphp.fr.

Abstract

BACKGROUND:

Ivacaftor-lumacaftor combination therapy corrects the F508 del-CFTR mutated protein which causes Cystic Fibrosis. The clinical response of the patients treated with the combination therapy is highly variable. This study aimed to determine factors involved in the individual's response to lumacaftor-ivacaftor therapy.

METHODS:

Sweat test was assessed at baseline and after 6 months of ivacaftor-lumacaftor treatment in 41 homozygous F508del children and young adults. β-adrenergic peak sweat secretion, nasal potential difference (NPD) and intestinal current measurements (ICM) were performed in patients accepting these tests. Seric level of lumacaftor and ivacaftor were determined and additional CFTR variant were searched.

RESULTS:

Sweat chloride concentration significantly decreased after treatment, whereas the β-adrenergic peak sweat response did not vary in 9 patients who underwent these tests. The average level of F508del-CFTR activity rescue reached up to 15% of the normal level in intestinal epithelium, as studied by ICM in 12 patients (p = .03) and 20% of normal in the nasal epithelium in NPD tests performed in 21 patients (NS). There was no significant correlation between these changes and improvements in FEV1 at 6 months. Serum drug levels did not correlate with changes in FEV1, BMI-Zscore or other CFTR activity biomarkers. Additional exonic variants were identified in 4 patients. The F87L-I1027T-F508del-CFTR complex allele abolished the lumacaftor corrector effect.

CONCLUSION:

This observational study investigates a number of potential factors linked to the clinical response of F508del homozygous patients treated with lumacaftor-ivacaftor combination therapy. Lumacaftor and ivacaftor blood levels are not associated with the clinical response. Additional exonic variants may influence protein correction.

PMID:
30595473
DOI:
10.1016/j.jcf.2018.12.011

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