Juliette Berger1,2,3, Marie Vigan4,5, Bruno Pereira6, Thu Thuy Nguyen4, Roseline Froissart7, Nadia Belmatoug8, Florence Dalbiès9, Agathe Masseau10, Christian Rose11, Christine Serratrice12, Yves-Marie Pers13, Ivan Bertchansky14, Fabrice Camou15, Monia Bengherbia8, Céline Bourgne1,2, Catherine Caillaud16,17, Magali Pettazzoni7, Amina Berrahal1, Jérôme Stirnemann18, France Mentré4,5, Marc G Berger19,20,21. 1. Hématologie Biologique, CHU Clermont-Ferrand, CHU Estaing, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand Cedex 1, France. 2. Université Clermont Auvergne, Equipe d'Accueil 7453 CHELTER, CHU Estaing, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand Cedex 1, France. 3. CHU Clermont-Ferrand, CHU Estaing, CRB Auvergne, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand Cedex 1, France. 4. INSERM and University Paris Diderot, IAME, UMR 1137, Paris, France. 5. AP-HP, Department of Epidemiology, Biostatistic and Clinical Research, Bichat Hospital, 75018, Paris, France. 6. CHU Clermont-Ferrand, DRCI, CHU Montpied, 58 rue Montalembert, 63003, Clermont-Ferrand Cedex 1, France. 7. Hospices Civils de Lyon, Centre de Biologie et de Pathologie Est, Unité des Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Service de Biochimie et Biologie Moléculaire Grand Est, 69677, Bron, France. 8. Médecine Interne, AP-HP, Hôpital Beaujon, 100 boulevard Général Leclerc, 92110, Clichy, France. 9. Hématologie, CHRU Brest site Hôpital Morvan, 5 avenue Maréchal Foch, 29200, Brest, France. 10. Médecine Interne, CHU de Nantes, Hôtel-Dieu, 44093, Nantes, France. 11. Onco-Hématologie, Hôpital Saint-Vincent de Paul, boulevard de Belfort, 59000, Lille, France. 12. Hôpitaux Universitaires de Genève, Département de Médecine Interne, Hôpital des Trois-Chêne, Chemin du Pont-Bochet 3, Thônex, 1226, Geneva, Switzerland. 13. Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie University Hospital, 371 avenue du Doyen-Gaston-Giraud, 34295, Montpellier, France. 14. INSERM U1183, Saint-Eloi University Hospital, Montpellier, France. 15. Service de Médecine Interne et Maladies Infectieuses, CHU Bordeaux, Groupe Hospitalier Sud, avenue Magellan, 33604, Pessac Cedex, France. 16. INSERM U1151, Institut Necker Enfants Malades, Université Paris Descartes, Paris, France. 17. AP-HP, Hôpital Universitaire Necker Enfants Malades, Laboratoire de Biochimie, Métabolomique et Protéomique, 149 rue de Sèvres, 75005, Paris, France. 18. Département de Médecine Interne, Hôpitaux Universitaires de Genève, Gabrielle Perret Gentil 4, 1211, Geneva, Switzerland. 19. Hématologie Biologique, CHU Clermont-Ferrand, CHU Estaing, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand Cedex 1, France. mberger@chu-clermontferrand.fr. 20. Université Clermont Auvergne, Equipe d'Accueil 7453 CHELTER, CHU Estaing, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand Cedex 1, France. mberger@chu-clermontferrand.fr. 21. CHU Clermont-Ferrand, CHU Estaing, CRB Auvergne, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand Cedex 1, France. mberger@chu-clermontferrand.fr.
Abstract
BACKGROUND AND OBJECTIVES: Intravenous imiglucerase enzyme replacement therapy for Gaucher disease type 1 administered every 2 weeks is at variance with the imiglucerase plasma half-life of a few minutes. We hypothesized that studying the pharmacokinetics of imiglucerase in blood Gaucher disease type 1 monocytes would be more relevant for understanding enzyme replacement therapy responses. METHODS: Glucocerebrosidase intra-monocyte activity was studied by flow cytometry. The pharmacokinetics of imiglucerase was analyzed using a population-pharmacokinetic model from a cohort of 31 patients with Gaucher disease type 1 who either started or were receiving long-term treatment with imiglucerase. RESULTS: A pharmacokinetic analysis of imiglucerase showed a two-compartment model with a high peak followed by a two-phase exponential decay (fast phase half-life: 0.36 days; slow phase half-life: 9.7 days) leading to a median 1.4-fold increase in glucocerebrosidase intra-monocyte activity from the pre-treatment activity (p = 0.04). In patients receiving long-term treatment, for whom the imiglucerase dose per infusion was chosen on the basis of disease aggressiveness/response, imiglucerase clearance correlated with the administered dose. However, the residual glucocerebrosidase intra-monocyte activity value was dose independent, suggesting that the maintenance of imiglucerase residual activity is patient specific. Endogenous pre-treatment glucocerebrosidase intra-monocyte activity was the most informative single parameter for distinguishing patients without (n = 10) and with a clinical indication (n = 17) for starting enzyme replacement therapy (area under the receiver operating characteristic curve: 0.912; 95% confidence interval 0.8-1; p < 0.001), as confirmed also by a factorial analysis of mixed data. CONCLUSION: This study provides novel pharmacokinetic data that support current imiglucerase administration regimens and suggests the existence of a glucocerebrosidase activity threshold related to Gaucher disease type 1 aggressiveness. These findings can potentially improve Gaucher disease type 1 management algorithms and clinical decision making.
BACKGROUND AND OBJECTIVES: Intravenous imiglucerase enzyme replacement therapy for Gaucher disease type 1 administered every 2 weeks is at variance with the imiglucerase plasma half-life of a few minutes. We hypothesized that studying the pharmacokinetics of imiglucerase in blood Gaucher disease type 1 monocytes would be more relevant for understanding enzyme replacement therapy responses. METHODS:Glucocerebrosidase intra-monocyte activity was studied by flow cytometry. The pharmacokinetics of imiglucerase was analyzed using a population-pharmacokinetic model from a cohort of 31 patients with Gaucher disease type 1 who either started or were receiving long-term treatment with imiglucerase. RESULTS: A pharmacokinetic analysis of imiglucerase showed a two-compartment model with a high peak followed by a two-phase exponential decay (fast phase half-life: 0.36 days; slow phase half-life: 9.7 days) leading to a median 1.4-fold increase in glucocerebrosidase intra-monocyte activity from the pre-treatment activity (p = 0.04). In patients receiving long-term treatment, for whom the imiglucerase dose per infusion was chosen on the basis of disease aggressiveness/response, imiglucerase clearance correlated with the administered dose. However, the residual glucocerebrosidase intra-monocyte activity value was dose independent, suggesting that the maintenance of imiglucerase residual activity is patient specific. Endogenous pre-treatment glucocerebrosidase intra-monocyte activity was the most informative single parameter for distinguishing patients without (n = 10) and with a clinical indication (n = 17) for starting enzyme replacement therapy (area under the receiver operating characteristic curve: 0.912; 95% confidence interval 0.8-1; p < 0.001), as confirmed also by a factorial analysis of mixed data. CONCLUSION: This study provides novel pharmacokinetic data that support current imiglucerase administration regimens and suggests the existence of a glucocerebrosidase activity threshold related to Gaucher disease type 1 aggressiveness. These findings can potentially improve Gaucher disease type 1 management algorithms and clinical decision making.
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