Dataset Information

Pharmacokinetic Modeling of Intrathecally Administered Recombinant Human Arylsulfatase A (TAK-611) in Children With Metachromatic Leukodystrophy.

ABSTRACT: 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.

SUBMITTER: Troy S

PROVIDER: S-EPMC7325319 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Pharmacokinetic Modeling of Intrathecally Administered Recombinant Human Arylsulfatase A (TAK-611) in Children With Metachromatic Leukodystrophy.

Troy Steven S Wasilewski Margaret M Beusmans Jack J Godfrey C J CJ

Clinical pharmacology and therapeutics 20200225 6

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 d ...[more]

PMID: 31868225

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Project description:ObjectiveWe aimed to gain more insight into the pathomechanisms of metachromatic leukodystrophy (MLD), by comparing magnitude and direction of diffusion between patients and controls at diagnosis and during follow-up.MethodsFour late-infantile, 16 juvenile and 8 adult onset MLD patients [of which 13 considered eligible for hematopoietic cell transplantation (HCT)] and 47 controls were examined using diffusion tensor imaging. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were quantified and compared between groups using tract-based spatial statistics (TBSS). Diffusion measures were determined for normal-appearing white matter (NAWM), corpus callosum, thalamus (all based on subject-wise segmentation), and pyramidal tracts, determined with probabilistic tractography. Measures were compared between HCT-eligible patients, non-eligible patients and controls using general linear model and nonparametric permutation analyses (randomise) for TBSS data, considering family-wise error corrected p < 0.05 significant.ResultsThroughout white matter (WM), FA was decreased and MD and RD increased in both patient groups compared to controls, while AD was decreased in NAWM and corpus callosum. In the thalamus, no differences in FA were observed, but all diffusivities were increased in both patient groups. Differences were most pronounced between controls and patients non-eligible for HCT. Longitudinally (median follow-up 3.9 years), diffusion measures remained relatively stable for HCT-treated patients, but were progressively abnormal for non-eligible patients.InterpretationThe observed diffusion measures confirm that brain microstructure is changed in MLD, reflecting different pathological processes including loss of myelin and sulfatide accumulation. The observation of both increased and decreased AD probably reflects a balance between myelin and axonal loss vs. intracellular sulfatide storage in macrophages, depending on region and disease stage.

Project description:Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase A (ASA), resulting in impaired degradation of sulfatide, an essential sphingolipid of myelin. The clinical manifestations of MLD are characterized by progressive demyelination and subsequent neurological symptoms resulting in severe debilitation. The availability of therapeutic options for treating MLD is limited but expanding with a number of early stage clinical trials already in progress. In the development of therapeutic approaches for MLD, scientists have been facing a number of challenges including blood-brain barrier (BBB) penetration, safety issues concerning therapies targeting the central nervous system, uncertainty regarding the ideal timing for intervention in the disease course, and the lack of more in-depth understanding of the molecular pathogenesis of MLD. Here, we discuss the current status of the different approaches to developing therapies for MLD. Hematopoietic stem cell transplantation has been used to treat MLD patients, utilizing both umbilical cord blood and bone marrow sources. Intrathecal enzyme replacement therapy and gene therapies, administered locally into the brain or by generating genetically modified hematopoietic stem cells, are emerging as novel strategies. In pre-clinical studies, different cell delivery systems including microencapsulated cells or selectively neural cells have shown encouraging results. Small molecules that are more likely to cross the BBB can be used as enzyme enhancers of diverse ASA mutants, either as pharmacological chaperones, or proteostasis regulators. Specific small molecules may also be used to reduce the biosynthesis of sulfatides, or target different affected downstream pathways secondary to the primary ASA deficiency. Given the progressive neurodegenerative aspects of MLD, also seen in other lysosomal diseases, current and future therapeutic strategies will be complementary, whether used in combination or separately at specific stages of the disease course, to produce better outcomes for patients afflicted with this devastating inherited disorder.

Dataset Information

Pharmacokinetic Modeling of Intrathecally Administered Recombinant Human Arylsulfatase A (TAK-611) in Children With Metachromatic Leukodystrophy.

Publications

Pharmacokinetic Modeling of Intrathecally Administered Recombinant Human Arylsulfatase A (TAK-611) in Children With Metachromatic Leukodystrophy.

Similar Datasets

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