A Quantitative Systems Pharmacology Model of Gaucher Disease Type 1 Provides Mechanistic Insight Into the Response to Substrate Reduction Therapy With Eliglustat

CPT Pharmacometrics Syst Pharmacol. 2020 Jul;9(7):374-383. doi: 10.1002/psp4.12506. Epub 2020 Jun 19.


Gaucher's disease type 1 (GD1) leads to significant morbidity and mortality through clinical manifestations, such as splenomegaly, hematological complications, and bone disease. Two types of therapies are currently approved for GD1: enzyme replacement therapy (ERT), and substrate reduction therapy (SRT). In this study, we have developed a quantitative systems pharmacology (QSP) model, which recapitulates the effects of eliglustat, the only first-line SRT approved for GD1, on treatment-naïve or patients with ERT-stabilized adult GD1. This multiscale model represents the mechanism of action of eliglustat that leads toward reduction of spleen volume. Model capabilities were illustrated through the application of the model to predict ERT and eliglustat responses in virtual populations of adult patients with GD1, representing patients across a spectrum of disease severity as defined by genotype-phenotype relationships. In summary, the QSP model provides a mechanistic computational platform for predicting treatment response via different modalities within the heterogeneous GD1 patient population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Enzyme Inhibitors / pharmacology
  • Gaucher Disease / drug therapy*
  • Gaucher Disease / physiopathology
  • Humans
  • Models, Biological*
  • Pyrrolidines / pharmacology*
  • Severity of Illness Index
  • Splenomegaly / drug therapy
  • Splenomegaly / etiology
  • Systems Biology*
  • Treatment Outcome


  • Enzyme Inhibitors
  • Pyrrolidines
  • eliglustat