Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by deficient arylsulfatase A (ASA) activity, which leads to neuronal sulfatide accumulation and motor and cognitive deterioration. Intrathecal delivery of a recombinant human ASA (TAK-611, formerly SHP611) is under development as a potential therapy for MLD. We used serum and cerebrospinal fluid (CSF) TAK-611 concentrations measured during the phase I/II trial of intrathecal TAK-611 to develop a pharmacokinetic (PK) model describing drug disposition. CSF data were well characterized by a two-compartment model in the central nervous system (CNS); a single central compartment described the serum data. Estimated parameters suggested rapid distribution of TAK-611 from CSF into the putative brain tissue compartment, with persistence in the brain between doses (median distributive and terminal half-lives in the CNS: 1.02 and 477 hours, respectively). This model provides a valuable basis for understanding the PK distribution of TAK-611 and for PK/pharmacodynamic analyses of functional outcomes.

中文翻译：

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鞘内施用重组人芳基硫酸酯酶A（TAK-611）在异色性白细胞营养不良儿童中的药代动力学模型。

变色性脑白质营养不良（MLD）是一种溶酶体贮积病，由芳基硫酸酯酶A（ASA）活性不足引起，可导致神经元硫酸脂累积以及运动和认知能力下降。鞘内递送重组人ASA（TAK-611，以前为SHP611）正在开发作为MLD的潜在疗法。我们使用鞘内TAK-611的I / II期临床试验期间测得的血清和脑脊髓液（CSF）TAK-611浓度建立描述药物处置的药代动力学（PK）模型。CSF数据通过中枢神经系统（CNS）的两室模型得到了很好的表征。一个中央隔室描述了血清数据。估计参数表明TAK-611从CSF迅速分布到假定的脑组织区室，在剂量之间会持续存在大脑（中枢神经系统的中位分布半衰期和终末半衰期分别为1.02和477小时）。该模型为理解TAK-611的PK分布以及功能预后的PK /药效分析提供了宝贵的基础。