Nadia Belmatoug1, Maja Di Rocco2, Cristina Fraga3, Pilar Giraldo4, Derralynn Hughes5, Elena Lukina6, Pierre Maison-Blanche7, Martin Merkel8, Claus Niederau9, Ursula Plӧckinger10, Johan Richter11, Thomas M Stulnig12, Stephan Vom Dahl13, Timothy M Cox14. 1. Referral Center for Lysosomal Diseases, University Beaujon Hospital Paris Nord Val de Seine, Assistance-Publique Hôpitaux de Paris, Department of Internal Medicine, 100 Boulevard du Général Leclerc, 92110 Clichy, France. Electronic address: nadia.belmatoug@aphp.fr. 2. Unit of Rare Diseases, Department Pediatrics, Gaslini Institute, Largo Gaslini 3, 16147 Genoa, Italy. Electronic address: majadirocco@ospedale-gaslini.ge.it. 3. Department of Haematology, HDES Hospital, Ponta Delgada, Av. D. Manuel I, PDL, Açores, Portugal. Electronic address: maria.cf.barros@azores.gov.pt. 4. Translational Research Unit, Instituto Investigación Sanitaria Aragon, CIBER Enfermedades Raras (CIBERER), Zaragoza, Spain. Electronic address: giraldocastellano@gmail.com. 5. Royal Free London NHS Foundation Trust, University College London, Department of Haematology, Pond St., London NW1 2QG, United Kingdom. 6. Department of Orphan Diseases, Hematology Research Center, 4 Novy Zykovsky Lane, 125167 Moscow, Russia. Electronic address: elenalukina02@gmail.com. 7. Bichat University Hospital, Cardiology Unit, 46 Rue Henri Huchard, 75018 Paris, France. Electronic address: ipmb@wanadoo.fr. 8. Department of Internal Medicine, Asklepios Klinik St. Georg, Lohmühlenstr. 5, 20099 Hamburg, Germany. Electronic address: m.merkel@asklepios.com. 9. Katholisches Klinikum Oberhausen GmbH, St. Josef Hospital, Department of Medicine, Academic Teaching Hospital, Universität Duisburg-Essen, Mülheimer Str. 83, 46045 Oberhausen, Germany. Electronic address: c.niederau@kk-ob.de. 10. Interdisziplinares Stoffwechsel-Centrum: Diabetes, Endokrinologie und Stoffwechsel, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13352 Berlin, Germany. Electronic address: ursula.ploeckinger@charite.de. 11. Department of Hematology and Vascular Diseases, Skåne University Hospital, 221 85 Lund, Sweden. Electronic address: johan.richter@med.lu.se. 12. Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Electronic address: thomas.stulnig@meduniwien.ac.at. 13. Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, University of Duesseldorf, Moorenstrasse 5, D-40225, Germany. Electronic address: Stephan.vomdahl@med.uni-duesseldorf.de. 14. Department of Medicine, University of Cambridge, Box 157, Level 5, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom. Electronic address: tmc12@medschl.cam.ac.uk.
Abstract
PURPOSE: In Gaucher disease, diminished activity of the lysosomal enzyme, acid β-glucosidase, leads to accumulation of glucosylceramides and related substrates, primarily in the spleen, liver, and bone marrow. Eliglustat is an oral substrate reduction therapy approved in the European Union and the United States as a first-line treatment for adults with type 1 Gaucher disease who have compatible CYP2D6 metabolism phenotypes. A European Advisory Council of experts in Gaucher disease describes the characteristics of eliglustat that are distinct from enzyme augmentation therapy (the standard of care) and miglustat (the other approved substrate reduction therapy) and recommends investigations and monitoring for patients on eliglustat therapy within the context of current recommendations for Gaucher disease management. RESULTS: Eliglustat is a selective, potent inhibitor of glucosylceramide synthase, the enzyme responsible for biosynthesis of glucosylceramides which accumulate in Gaucher disease. Extensive metabolism of eliglustat by CYP2D6, and, to a lesser extent, CYP3A of the cytochrome P450 pathway, necessitates careful consideration of the patient's CYP2D6 metaboliser status and use of concomitant medications which share metabolism by these pathways. Guidance on specific assessments and monitoring required for eliglustat therapy, including an algorithm to determine eligibility for eliglustat, are provided. CONCLUSIONS: As a first-line therapy for type 1 Gaucher disease, eliglustat offers eligible patients a daily oral therapy alternative to biweekly infusions of enzyme therapy. Physicians will need to carefully assess individual Gaucher patients to determine their appropriateness for eliglustat therapy. The therapeutic response to eliglustat and use of concomitant medications will require long-term monitoring.
PURPOSE: In Gaucher disease, diminished activity of the lysosomal enzyme, acid β-glucosidase, leads to accumulation of glucosylceramides and related substrates, primarily in the spleen, liver, and bone marrow. Eliglustat is an oral substrate reduction therapy approved in the European Union and the United States as a first-line treatment for adults with type 1 Gaucher disease who have compatible CYP2D6 metabolism phenotypes. A European Advisory Council of experts in Gaucher disease describes the characteristics of eliglustat that are distinct from enzyme augmentation therapy (the standard of care) and miglustat (the other approved substrate reduction therapy) and recommends investigations and monitoring for patients on eliglustat therapy within the context of current recommendations for Gaucher disease management. RESULTS: Eliglustat is a selective, potent inhibitor of glucosylceramide synthase, the enzyme responsible for biosynthesis of glucosylceramides which accumulate in Gaucher disease. Extensive metabolism of eliglustat by CYP2D6, and, to a lesser extent, CYP3A of the cytochrome P450 pathway, necessitates careful consideration of the patient's CYP2D6 metaboliser status and use of concomitant medications which share metabolism by these pathways. Guidance on specific assessments and monitoring required for eliglustat therapy, including an algorithm to determine eligibility for eliglustat, are provided. CONCLUSIONS: As a first-line therapy for type 1 Gaucher disease, eliglustat offers eligible patients a daily oral therapy alternative to biweekly infusions of enzyme therapy. Physicians will need to carefully assess individual Gaucher patients to determine their appropriateness for eliglustat therapy. The therapeutic response to eliglustat and use of concomitant medications will require long-term monitoring.
Authors: Francesca Gorini; Michele Santoro; Anna Pierini; Lorena Mezzasalma; Silvia Baldacci; Elena Bargagli; Alessandra Boncristiano; Maurizia Rossana Brunetto; Paolo Cameli; Francesco Cappelli; Giancarlo Castaman; Barbara Coco; Maria Alice Donati; Renzo Guerrini; Silvia Linari; Vittoria Murro; Iacopo Olivotto; Paola Parronchi; Francesca Pochiero; Oliviero Rossi; Barbara Scappini; Andrea Sodi; Alessandro Maria Vannucchi; Alessio Coi Journal: Front Pharmacol Date: 2022-05-16 Impact factor: 5.988
Authors: Timothy M Cox; Guillermo Drelichman; Renata Cravo; Manisha Balwani; Thomas Andrew Burrow; Ana Maria Martins; Elena Lukina; Barry Rosenbloom; Ozlem Goker-Alpan; Nora Watman; Amal El-Beshlawy; Priya S Kishnani; Maria Lucia Pedroso; Sebastiaan J M Gaemers; Regina Tayag; M Judith Peterschmitt Journal: Blood Date: 2017-02-06 Impact factor: 22.113