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- Title
Intra-monocyte Pharmacokinetics of Imiglucerase Supports a Possible Personalized Management of Gaucher Disease Type 1.
- Authors
Berger, Juliette; Vigan, Marie; Pereira, Bruno; Nguyen, Thu Thuy; Froissart, Roseline; Belmatoug, Nadia; Dalbiès, Florence; Masseau, Agathe; Rose, Christian; Serratrice, Christine; Pers, Yves-Marie; Bertchansky, Ivan; Camou, Fabrice; Bengherbia, Monia; Bourgne, Céline; Caillaud, Catherine; Pettazzoni, Magali; Berrahal, Amina; Stirnemann, Jérôme; Mentré, France
- Abstract
<bold>Background and Objectives: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
GAUCHER'S disease; PHARMACOKINETICS; ANEMIA; CHEMICAL kinetics; CLINICAL trials
- Publication
Clinical Pharmacokinetics, 2019, Vol 58, Issue 4, p469
- ISSN
0312-5963
- Publication type
journal article
- DOI
10.1007/s40262-018-0708-8