4.5 Article

Quantitative assessment of the exposure-efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy

期刊

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
卷 88, 期 6, 页码 2727-2737

出版社

WILEY
DOI: 10.1111/bcp.15198

关键词

Gaucher disease; glucocerebrosidase; Markov-time discrete model; pharmacokinetics

资金

  1. Generalitat Valenciana

向作者/读者索取更多资源

A population pharmacokinetic model of enzyme activity in Gaucher-type 1 (GD1) patients after intravenous administration of enzyme replacement therapy (ERT) was developed, and an exposure-efficacy relationship for bone marrow infiltration was established. The findings of this study are of significant clinical relevance for the individualization of ERT in GD1 patients.
Aims The aims of this study are (i) to develop a population pharmacokinetic model of enzyme activity in Gaucher-type 1 (GD1) patients after intravenous administration of enzyme replacement therapy (ERT), and (ii) to establish an exposure-efficacy relationship for bone marrow infiltration to propose dose adjustments according to patient covariate values. Methods A prospective follow-up, semi-experimental multi-centre study was conducted in four hospitals to evaluate the pharmacokinetics, efficacy and safety of ERT in GD1 patients. Twenty-five individuals with 266 glucocerebrosidase (GCase) observations in plasma and leukocytes and 14 individuals with 68 Spanish magnetic resonance imaging (S-MRI) observations were enrolled. Results A two concatenated compartment model with zero-order endogenous production and first-order distribution (CL1 = 3.85 x 10(-1) L/d) and elimination (CL2 = 1.25 L/d) allowed GCase observations in plasma and leukocytes to be described, respectively. An exponential time dependency (k(T) = 6.14 x 10(-1) d(-1)) effect on CL1 was incorporated. The final exposure-efficacy model was a longitudinal logistic regression model with a first-order Markov element. An E-max function (EC50 = 15.73 U/L and E-max = 2.33) linked steady-state concentrations of GCase in leukocytes to the probability of transition across the different S-MRI stages. Conclusion A population pharmacokinetic model successfully characterized the leukocyte activity-time profiles of GCase following intravenous administration of ERT in GD1 patients together with an exposure-efficacy relationship in bone marrow using Markovian elements. The information obtained from this study could be of high clinical relevance in individualization of ERT in GD1 patients, as this could lead to anticipative decision-making regarding clinical response in bone and optimal dosing strategy.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.5
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据