{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T05:01:41Z","timestamp":1787893301387,"version":"build-2784847793"},"reference-count":25,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,3,29]],"date-time":"2017-03-29T00:00:00Z","timestamp":1490745600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population\u2010based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4\u2010compartment model simultaneously described the time\u2010concentration profiles in both matrices. The typical population parameters were: Q\n                    <jats:sub>p<\/jats:sub>\n                    = 0.572 L\/h, Q\n                    <jats:sub>CSF<\/jats:sub>\n                    = 0.069 L\/h, CL\n                    <jats:sub>p<\/jats:sub>\n                    = 2.50 L\/h, CL\n                    <jats:sub>CSF<\/jats:sub>\n                    = 0.133 L\/hr, V\n                    <jats:sub>CSF<\/jats:sub>\n                    = 0.441 L, V\n                    <jats:sub>p<\/jats:sub>\n                    = 32.0 L, V\n                    <jats:sub>systemic_tissue<\/jats:sub>\n                    = 429 L, and V\n                    <jats:sub>CNS_tissue<\/jats:sub>\n                    = 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on V\n                    <jats:sub>CSF<\/jats:sub>\n                    , V\n                    <jats:sub>p<\/jats:sub>\n                    , and CL\n                    <jats:sub>p<\/jats:sub>\n                    . The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children &gt;2 years. Simulations from the final model showed that age\u2010based dosing in children under 2 years ensured a more comparable exposure (peak concentration and area under the concentration\u2010time curve) across subjects in the population relative to a fixed dosing scheme. However, because no dose\u2010limiting toxicity has been reported in any of the trials, a fixed\u2010dose scheme (12 mg across all age groups) was recommended. The median terminal half\u2010life of nusinersen in the CSF was determined from the model to be 163 days, which supported infrequent dosing, once every 4 to 6 months in pediatric patients with spinal muscular atrophy.\n                  <\/jats:p>","DOI":"10.1002\/jcph.884","type":"journal-article","created":{"date-parts":[[2017,3,29]],"date-time":"2017-03-29T10:57:52Z","timestamp":1490785072000},"page":"1031-1041","source":"Crossref","is-referenced-by-count":57,"title":["Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations"],"prefix":"10.1002","volume":"57","author":[{"given":"Kenneth T.","family":"Luu","sequence":"first","affiliation":[{"name":"Pharmacokinetics and Clinical Pharmacology Ionis Pharmaceuticals Carlsbad CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Norris","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and Clinical Pharmacology Ionis Pharmaceuticals Carlsbad CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudy","family":"Gunawan","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and Clinical Pharmacology Ionis Pharmaceuticals Carlsbad CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Henry","sequence":"additional","affiliation":[{"name":"Nonclinical Development Ionis Pharmaceuticals Carlsbad CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Geary","sequence":"additional","affiliation":[{"name":"Clinical Development Ionis Pharmaceuticals Carlsbad CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and Clinical Pharmacology Ionis Pharmaceuticals Carlsbad CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,3,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-71"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00197416"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.4137\/JEN.S33122"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1090-3798(99)80012-9"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.1996.0010"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1509758112"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1941310"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002445"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/11.4.335"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9255-z"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01113502"},{"key":"e_1_2_7_13_1","article-title":"A full model estimation approach for covariate effects: inference based on clinical importance and estimation precision [abstract]","volume":"6","author":"Gastonguay M.","year":"2004","journal-title":"AAPS J"},{"key":"e_1_2_7_14_1","volume-title":"Pharmacokinetic and Pharmacodynamic Data Analysis","author":"Gabrielsson JW","year":"2000"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2009.03.009"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10897-016-9955-8"},{"key":"e_1_2_7_17_1","doi-asserted-by":"crossref","unstructured":"FinkelR Chiriboga CA Vjsar J et\u00a0al.Interim results of a phase 2 clinical study of nusinersen (ISIS\u2010SMNRx) in patients with infantile\u2010onset spinal muscular atrophy (AAN 2016 Poster P5.004). Poster presented at: 68th Annual American Academy of Neurology.","DOI":"10.1212\/WNL.86.16_supplement.P5.004"},{"key":"e_1_2_7_18_1","volume-title":"Spinal Cerebral Fluid Chemistry and Physiology","author":"Artru AA","year":"1999"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/2045-8118-11-10"},{"key":"e_1_2_7_20_1","volume-title":"Pediatric Anesthesia","author":"Bissonnette B","year":"2014"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.113.212407"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-014-9398-5"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2015.01.008"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-010-9184-y"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200003000-00018"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-8454-5-10"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcph.884","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.884","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,23]],"date-time":"2024-06-23T05:40:38Z","timestamp":1719121238000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,29]]},"references-count":25,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017,8]]}},"alternative-id":["10.1002\/jcph.884"],"URL":"https:\/\/doi.org\/10.1002\/jcph.884","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,29]]}}}