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

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.

• Authors: 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
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 58 Issue 4 Pg. 469-482 (04 2019) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 30128966 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Glucosylceramidase
• imiglucerase

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Child
• Enzyme Replacement Therapy
• Female
• Gaucher Disease (drug therapy, metabolism)
• Glucosylceramidase (metabolism, pharmacokinetics, therapeutic use)
• Humans
• Male
• Middle Aged
• Models, Biological
• Monocytes (metabolism)
• Precision Medicine
• Young Adult