Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology
Open accessAbstract
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.
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Flagged first, then by citations
Research works printed but not linked: 1
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Cited by
Sorted by citations
Kirouac, D. C., Cicali, B., & Schmidt, S. (2019) · CPT: Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12390 · Cited by 46 · see citing works
“Pharmacokinetic/pharmacodynamic plots generated from Kadidi et al.(14) model.”
Method
- Authors
- Kaddi, C. D., Niesner, B., Baek, R., Jasper, P., Pappas, J., Tolsma, J., Li, J., van Rijn, Z., Tao, M., Ortemann‐Renon, C., Easton, R., Tan, S., Puga, A. C., Schuchman, E. H., Barrett, J. S., & Azer, K.
- Affiliations
- Sanofi (United States) (US)
- Sanofi Genzyme, Cambridge Massachusetts USA
- Renewable Energy Systems (United States) (US)
- Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Azer, Karim
- Venue
- CPT: Pharmacometrics & Systems Pharmacology
- Publisher
- Wiley
- Published
- 2018-06-19
- Volume
- 7
- Issue
- 7
- Pages
- 442-452
- ISSN
- 2163-8306 (ISSN-L)
- PMC
- PMC6063739
- OpenAlex
- W2809088929
- Cited by
- 36
- References
- 43
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 8 · 2022: 2 · 2021: 6 · 2020: 1 · 2019: 7
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- CPT Pharmacometrics & Systems Pharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD028607)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- acid sphingomyelinase deficiency, olipudase alfa, enzyme replacement therapy, lysosomal storage disease, pharmacodynamics, natural history (disease), disease severity markers
- MeSH terms
- Animals, Calibration, Humans, Models, Biological, Niemann-Pick Diseases, Recombinant Proteins, Sphingomyelin Phosphodiesterase, Mice, Knockout, Mice, Enzyme Replacement Therapy
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