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Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology.
CPT Pharmacometrics Syst Pharmacol. 2018 07; 7(7):442-452.CP

Abstract

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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Authors+Show Affiliations

Kaddi CD
Translational Informatics, TMED, Sanofi, Bridgewater, New Jersey, USA.
Niesner B
Translational Informatics, TMED, Sanofi, Bridgewater, New Jersey, USA.
Baek R
Sanofi Genzyme, Cambridge, Massachusetts, USA.
Jasper P
RES Group Inc., Needham, Massachusetts, USA.
Pappas J
RES Group Inc., Needham, Massachusetts, USA.
Tolsma J
RES Group Inc., Needham, Massachusetts, USA.
Li J
Translational Informatics, TMED, Sanofi, Bridgewater, New Jersey, USA.
van Rijn Z
Translational Informatics, TMED, Sanofi, Bridgewater, New Jersey, USA.
Tao M
Translational Informatics, TMED, Sanofi, Bridgewater, New Jersey, USA.
Ortemann-Renon C
Translational Informatics, TMED, Sanofi, Bridgewater, New Jersey, USA.
Easton R
Translational Informatics, TMED, Sanofi, Bridgewater, New Jersey, USA.
Tan S
Sanofi Genzyme, Cambridge, Massachusetts, USA.
Puga AC
Sanofi Genzyme, Cambridge, Massachusetts, USA.
Schuchman EH
Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Barrett JS
Translational Informatics, TMED, Sanofi, Bridgewater, New Jersey, USA.
Azer K
Translational Informatics, TMED, Sanofi, Bridgewater, New Jersey, USA.

MeSH

AnimalsCalibrationEnzyme Replacement TherapyHumansMiceMice, KnockoutModels, BiologicalNiemann-Pick DiseasesRecombinant ProteinsSphingomyelin Phosphodiesterase

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29920993

Citation

Kaddi, Chanchala D., et al. "Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology." CPT: Pharmacometrics & Systems Pharmacology, vol. 7, no. 7, 2018, pp. 442-452.
Kaddi CD, Niesner B, Baek R, et al. Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology. CPT Pharmacometrics Syst Pharmacol. 2018;7(7):442-452.
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. (2018). Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology. CPT: Pharmacometrics & Systems Pharmacology, 7(7), 442-452. https://doi.org/10.1002/psp4.12304
Kaddi CD, et al. Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology. CPT Pharmacometrics Syst Pharmacol. 2018;7(7):442-452. PubMed PMID: 29920993.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology. AU - Kaddi,Chanchala D, AU - Niesner,Bradley, AU - Baek,Rena, AU - Jasper,Paul, AU - Pappas,John, AU - Tolsma,John, AU - Li,Jing, AU - van Rijn,Zachary, AU - Tao,Mengdi, AU - Ortemann-Renon,Catherine, AU - Easton,Rachael, AU - Tan,Sharon, AU - Puga,Ana Cristina, AU - Schuchman,Edward H, AU - Barrett,Jeffrey S, AU - Azer,Karim, Y1 - 2018/06/19/ PY - 2018/01/26/received PY - 2018/03/27/revised PY - 2018/04/10/accepted PY - 2018/6/20/pubmed PY - 2019/10/29/medline PY - 2018/6/20/entrez SP - 442 EP - 452 JF - CPT: pharmacometrics & systems pharmacology JO - CPT Pharmacometrics Syst Pharmacol VL - 7 IS - 7 N2 - 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. SN - 2163-8306 UR - https://www.unboundmedicine.com/medline/citation/29920993/Quantitative_Systems_Pharmacology_Modeling_of_Acid_Sphingomyelinase_Deficiency_and_the_Enzyme_Replacement_Therapy_Olipudase_Alfa_Is_an_Innovative_Tool_for_Linking_Pathophysiology_and_Pharmacology_ DB - PRIME DP - Unbound Medicine ER -