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Intra-monocyte Pharmacokinetics of Imiglucerase Supports a Possible Personalized Management of Gaucher Disease Type 1

  • Juliette Berger
  • Marie Vigan
  • Bruno Pereira
  • Thu Thuy Nguyen
  • Roseline Froissart
  • Nadia Belmatoug
  • Florence Dalbiès
  • Agathe Masseau
  • Christian Rose
  • Christine Serratrice
  • Yves-Marie Pers
  • Ivan Bertchansky
  • Fabrice Camou
  • Monia Bengherbia
  • Céline Bourgne
  • Catherine Caillaud
  • Magali Pettazzoni
  • Amina Berrahal
  • Jérôme Stirnemann
  • France Mentré
  • Marc G. Berger
Original Research Article
  • 103 Downloads

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.

Notes

Acknowledgements

The authors thank Dominique Chadeyron supported by EA 7453 CHELTER, Université Clermont Auvergne, for secretarial assistance, Pascale Pigeon, Charlène Fernandez, Marine Mérat, Amélie Buffet, Caroline Jamot, and Nathalie Chaudagne, (Clermont-Ferrand University Hospital) for technical assistance; Baptiste Verdier, Sandrine Saugues, and Fanny Soulé, staff of the Centre de Ressources Biologiques Auvergne (CHU Estaing, Clermont-Fd) for the cryopreservation of human samples. Marc G. Berger and Juliette Berger would like to express on behalf of the authors their gratitude to the patients, nurses, and local biologists who participated in the successful completion of this study. We also thank Dr. Bruno Padrazzi and Rachel Sembeil who facilitated the initial exchanges between the collaborating teams of this study.

Author contributions

JB organized logistical support for sending samples, performed the experiments, and analyzed some data with MGB MV, TTN, and FM carried out the population-pharmacokinetic modeling and participated in the statistical analysis. BP contributed to the statistical analysis. RF, CC, and MP performed the genotype and biomarker assays. CB assisted with the flow cytometry experiments and CCL18 assays. NB, FD, AM, CR, CS, YMP, IB, FB, JS, and MGB recruited patients. MB and AB assisted in collecting related clinical and biological data. MV, FM, BP, and MGB designed the figures and wrote the paper. MGB and FM designed the research project, supervised the study, analyzed data, and revised the paper.

Compliance with ethical standards

Funding

This study was supported by grants from Genzyme SA then Sanofi-Genzyme (Grant no. GZ-2010-10458) and from Vaincre les Maladies Lysosomales (patient association, Paris, France) (Grant no. VML S9MBerger) and research funding from CHU de Clermont-Ferrand as the promotor establishment, Marc G. Berger being an investigator coordinator (Grant no. PHRC2010-AOI MBerger).

Conflict of interest

Nadia Belmatoug, Christian Rose, Marc G. Berger, and Christine Serratrice received honoraria from Sanofi-Genzyme and Shire Corporation for travel and speaking or expert missions; Yves-Marie Pers and Jérôme Stirnemann received travel fees from Sanofi-Genzyme. Nadia Belmatoug, Christian Rose, and Marc G. Berger are scientific leaders of research projects receiving research grants from Sanofi-Genzyme and Shire Corporation. Christian Rose is a scientific leader of a research project receiving research grants from Sanofi-Genzyme. Nadia Belmatoug, Christine Serratrice, Fabrice Camou, and Marc G. Berger are members of the scientific board organized by Sanofi-Genzyme, Shire; Juliette Berger, Marie Vigan, Bruno Pereira, Thu Thuy Nguyen, Roseline Froissart, Florence Dalbiès, Agathe Masseau, Yves-Marie Pers, Ivan Bertchansky, Monia Bengherbia, Céline Bourgne, Catherine Caillaud, Magali Pettazzoni, Amina Berrahal, and France Mentré have no conflicts of interest directly relevant to the contents of this article.

Supplementary material

40262_2018_708_MOESM1_ESM.doc (979 kb)
Supplementary material 1 (DOC 979 kb)

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Juliette Berger
    • 1
    • 2
    • 3
  • Marie Vigan
    • 4
    • 5
  • Bruno Pereira
    • 6
  • Thu Thuy Nguyen
    • 4
  • Roseline Froissart
    • 7
  • Nadia Belmatoug
    • 8
  • Florence Dalbiès
    • 9
  • Agathe Masseau
    • 10
  • Christian Rose
    • 11
  • Christine Serratrice
    • 12
  • Yves-Marie Pers
    • 13
  • Ivan Bertchansky
    • 14
  • Fabrice Camou
    • 15
  • Monia Bengherbia
    • 8
  • Céline Bourgne
    • 1
    • 2
  • Catherine Caillaud
    • 16
    • 17
  • Magali Pettazzoni
    • 7
  • Amina Berrahal
    • 1
  • Jérôme Stirnemann
    • 18
  • France Mentré
    • 4
    • 5
  • Marc G. Berger
    • 1
    • 2
    • 3
  1. 1.Hématologie Biologique, CHU Clermont-Ferrand, CHU EstaingClermont-Ferrand Cedex 1France
  2. 2.Université Clermont Auvergne, Equipe d’Accueil 7453 CHELTER, CHU EstaingClermont-Ferrand Cedex 1France
  3. 3.CHU Clermont-Ferrand, CHU Estaing, CRB AuvergneClermont-Ferrand Cedex 1France
  4. 4.INSERM and University Paris Diderot, IAME, UMR 1137ParisFrance
  5. 5.AP-HP, Department of Epidemiology, Biostatistic and Clinical ResearchBichat HospitalParisFrance
  6. 6.CHU Clermont-Ferrand, DRCI, CHU MontpiedClermont-Ferrand Cedex 1France
  7. 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 EstBronFrance
  8. 8.Médecine Interne, AP-HP, Hôpital BeaujonClichyFrance
  9. 9.Hématologie, CHRU Brest site Hôpital MorvanBrestFrance
  10. 10.Médecine Interne, CHU de Nantes, Hôtel-DieuNantesFrance
  11. 11.Onco-Hématologie, Hôpital Saint-Vincent de Paul, boulevard de BelfortLilleFrance
  12. 12.Hôpitaux Universitaires de Genève, Département de Médecine Interne, Hôpital des Trois-ChêneGenevaSwitzerland
  13. 13.Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie University HospitalMontpellierFrance
  14. 14.INSERM U1183, Saint-Eloi University HospitalMontpellierFrance
  15. 15.Service de Médecine Interne et Maladies InfectieusesCHU Bordeaux, Groupe Hospitalier Sud, avenue MagellanPessac CedexFrance
  16. 16.INSERM U1151, Institut Necker Enfants Malades, Université Paris DescartesParisFrance
  17. 17.AP-HP, Hôpital Universitaire Necker Enfants Malades, Laboratoire de Biochimie, Métabolomique et ProtéomiqueParisFrance
  18. 18.Département de Médecine Interne, Hôpitaux Universitaires de GenèveGenevaSwitzerland

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