Open AccessQuantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology
Author(s) -
Kaddi Chanchala D.,
Niesner Bradley,
Baek Rena,
Jasper Paul,
Pappas John,
Tolsma John,
Li Jing,
van Rijn Zachary,
Tao Mengdi,
OrtemannRe Catherine,
Easton Rachael,
Tan Sharon,
Puga Ana Cristina,
Schuchman Edward H.,
Barrett Jeffrey S.,
Azer Karim
Publication year - 2018
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12304
Subject(s) - enzyme replacement therapy , acid sphingomyelinase , pharmacology , medicine , pharmacokinetics , disease , pharmacodynamics , clinical pharmacology , sphingomyelin , cholesterol
Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non‐neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular‐level, cellular‐level, and organ‐level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient‐specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics.