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Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non\u2010neurological 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\u2010level, cellular\u2010level, and organ\u2010level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient\u2010specific 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.<\/jats:p>","DOI":"10.1002\/psp4.12304","type":"journal-article","created":{"date-parts":[[2018,6,19]],"date-time":"2018-06-19T20:55:25Z","timestamp":1529441725000},"page":"442-452","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology"],"prefix":"10.1002","volume":"7","author":[{"given":"Chanchala D.","family":"Kaddi","sequence":"first","affiliation":[{"name":"Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Niesner","sequence":"additional","affiliation":[{"name":"Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rena","family":"Baek","sequence":"additional","affiliation":[{"name":"Sanofi Genzyme, Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Jasper","sequence":"additional","affiliation":[{"name":"RES Group Inc., Needham  Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Pappas","sequence":"additional","affiliation":[{"name":"RES Group Inc., Needham  Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Tolsma","sequence":"additional","affiliation":[{"name":"RES Group Inc., Needham  Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"van Rijn","sequence":"additional","affiliation":[{"name":"Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdi","family":"Tao","sequence":"additional","affiliation":[{"name":"Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Ortemann\u2010Renon","sequence":"additional","affiliation":[{"name":"Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Easton","sequence":"additional","affiliation":[{"name":"Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Tan","sequence":"additional","affiliation":[{"name":"Sanofi Genzyme, Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Cristina","family":"Puga","sequence":"additional","affiliation":[{"name":"Sanofi Genzyme, Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward H.","family":"Schuchman","sequence":"additional","affiliation":[{"name":"Genetics &amp; Genomic Sciences, Icahn School of Medicine at Mount Sinai New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey S.","family":"Barrett","sequence":"additional","affiliation":[{"name":"Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Azer","sequence":"additional","affiliation":[{"name":"Translational Informatics, TMED, Sanofi, Bridgewater New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,6,19]]},"reference":[{"issue":"41","key":"e_1_2_9_1_1","article-title":"Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD)","volume":"12","author":"McGovern M.M.","year":"2017","journal-title":"Orphanet J. 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