Intra-monocyte Pharmacokinetics of Imiglucerase Supports a Possible Personalized Management of Gaucher Disease Type 1
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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.
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.
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.
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.
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.
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
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.
- 16.Sims KB, Pastores GM, Weinreb NJ, Barranger J, Rosenbloom BE, Packman S, et al. Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study. Clin Genet. 2008;73:430–40.CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Pettazzoni M, Froissart R, Pagan C, Vanier MT, Ruet S, Latour P, et al. LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: a novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease. PLoS One. 2017;12:e0181700.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Pagès J. Multiple factor analysis by example using R: Chapman and Hall/CRC, The R Series; 2014Google Scholar