Population Pharmacokinetic/Pharmacodynamic Modeling of Therapeutic Enzymes in Lysosomal Storage Diseases

BACKGROUND: Lysosomal storage diseases (LSDs) are rare genetic disorders treated with enzyme replacement therapy (ERT). However, treatment outcomes are highly variable, reflecting the complexities of therapeutic enzyme pharmacology, patient heterogeneity and therapy response. Population pharmacokinetic/pharmacodynamic (popPK/PD) modeling can help characterize this variability, identify covariates, and optimize dosing strategies. OBJECTIVES: This review aimed to provide a comprehensive overview of published popPK and popPD models of therapeutic enzymes in LSDs, summarize modeling strategies and study characteristics, and evaluate the quality of the available models. METHODS: A systematic search of Medline, Embase, and Web of Science (inception-March 2025) identified studies reporting popPK and/or popPD models of therapeutic enzymes in patients with LSDs. Data on study characteristics, structural and statistical model choices, covariate analyses, and evaluation methods were extracted and compared. RESULTS: ) model or by a longitudinal logistic regression model with a first-order Markov element. CONCLUSIONS: ) models to describe the delayed and saturable effects of ERT, and innovative approaches such as intracellular PK assessment and Markov modeling illustrate the potential of advanced pharmacometric methods. Nevertheless, there remains a need to further clarify the role of drug concentration measurements in target cells, to characterize CNS distribution in LSDs affecting the brain following intrathecal administration of ERTs and intravenous administration of a novel fusion protein, and to identify robust PD biomarkers in defining exposure-response relationships of therapeutic enzymes in LSDs.