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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.

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