{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:48:52Z","timestamp":1792172932444,"version":"4.4.0"},"reference-count":38,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2018,8,16]],"date-time":"2018-08-16T00:00:00Z","timestamp":1534377600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:p>A pharmacokinetic (<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>) model was developed for nusinersen, an antisense oligonucleotide (<jats:styled-content style=\"fixed-case\">ASO<\/jats:styled-content>) that is the first approved treatment for spinal muscular atrophy (SMA). The model was built with data from 92 nonhuman primates (NHPs) following intrathecal doses (0.3\u20137\u00a0mg) and characterized the <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content> in cerebrospinal fluid (<jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content>), plasma, total spinal cord, brain, and pons. The estimated volumes were 13.6, 937, 4.5, 53.8, and 2.11\u00a0mL, respectively. Global sensitivity analysis demonstrated that the <jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content>\u2010to\u2010plasma drug distribution rate (0.09\u00a0hour<jats:sup>\u22121<\/jats:sup>) is a major determinant of the maximum nusinersen concentration in central nervous system (CNS) tissues. Physiological age\u2010based and body weight\u2010based allometric scaling was implemented with exponent values of \u22120.08 and 1 for the rate constants and the volume of distribution, respectively. Simulations of the scaled model were in agreement with clinical observations from 52 pediatric phase I <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content> profiles. The developed model can be used to guide the design of clinical trials with <jats:styled-content style=\"fixed-case\">ASO<\/jats:styled-content>s.<\/jats:p>","DOI":"10.1002\/psp4.12323","type":"journal-article","created":{"date-parts":[[2018,7,25]],"date-time":"2018-07-25T04:25:56Z","timestamp":1532492756000},"page":"581-592","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["A Semi\u2010Mechanistic Population Pharmacokinetic Model of Nusinersen: An Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy"],"prefix":"10.1002","volume":"7","author":[{"given":"Konstantinos","family":"Biliouris","sequence":"first","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puneet","family":"Gaitonde","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yin","sequence":"additional","affiliation":[{"name":"Biogen Idec  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Norris","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals Inc.  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