{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T16:00:56Z","timestamp":1783526456983,"version":"3.55.0"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007013","name":"F. Hoffmann-La Roche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:p>Risdiplam (Evrysdi) improves motor neuron function in patients with spinal muscular atrophy (SMA) and has been approved for the treatment of patients \u22652\u00a0months old. Risdiplam exhibits time\u2010dependent inhibition of cytochrome P450 (CYP) 3A <jats:italic>in vitro<\/jats:italic>. While many pediatric patients receive risdiplam, a drug\u2013drug interaction (DDI) study in pediatric patients with SMA was not feasible. Therefore, a novel physiologically\u2010based pharmacokinetic (PBPK) model\u2010based strategy was proposed to extrapolate DDI risk from healthy adults to children with SMA in an iterative manner. A clinical DDI study was performed in healthy adults at relevant risdiplam exposures observed in children. Risdiplam caused an 1.11\u2010fold increase in the ratio of midazolam area under the curve with and without risdiplam (AUCR)), suggesting an 18\u2010fold lower <jats:italic>in vivo<\/jats:italic> CYP3A inactivation constant compared with the <jats:italic>in vitro<\/jats:italic> value. A pediatric PBPK model for risdiplam was validated with independent data and combined with a validated midazolam pediatric PBPK model to extrapolate DDI from adults to pediatric patients with SMA. The impact of selected intestinal and hepatic CYP3A ontogenies on the DDI susceptibility in children relative to adults was investigated. The PBPK analysis suggests that primary CYP3A inhibition by risdiplam occurs in the intestine rather than the liver. The PBPK\u2010predicted risdiplam CYP3A inhibition risk in pediatric patients with SMA aged 2\u00a0months\u201318\u00a0years was negligible (midazolam AUCR of 1.09\u20131.18) and included in the US prescribing information of risdiplam. Comprehensive evaluation of the sensitivity of predicted CYP3A DDI on selected intestinal and hepatic CYP3A ontogeny functions, together with PBPK model\u2010based strategy proposed here, aim to guide and facilitate DDI extrapolations in pediatric populations.<\/jats:p>","DOI":"10.1002\/cpt.2384","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T16:07:53Z","timestamp":1628093273000},"page":"1547-1557","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Model\u2010Based Drug\u2013Drug Interaction Extrapolation Strategy From Adults to Children: Risdiplam in Pediatric Patients With Spinal Muscular Atrophy"],"prefix":"10.1111","volume":"110","author":[{"given":"Yumi","family":"Cleary","sequence":"first","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Roche Innovation Center Basel Switzerland"},{"name":"Centre for Applied Pharmacokinetic Research University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gertz","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Roche Innovation Center Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Grimsey","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Roche Innovation Center Welwyn UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"G\u00fcnther","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Roche Innovation Center Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Heinig","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Roche Innovation Center Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayode","family":"Ogungbenro","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Aarons","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Galetin","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidemarie","family":"Kletzl","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Pharmaceutical Sciences Roche Innovation Center Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-71"},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90460-3"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70061-3"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00741"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000741"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2009965"},{"key":"e_1_2_11_7_1","unstructured":"US Food and Drug Administration.FDA approves oral treatment for spinal muscular atrophy<https:\/\/www.fda.gov\/news\u2010events\/press\u2010announcements\/fda\u2010approves\u2010oral\u2010treatment\u2010spinal\u2010muscular\u2010atrophy> (2020). Accessed March 2021."},{"key":"e_1_2_11_8_1","unstructured":"European Medicines Agency. Summary of opintion (initial authorisation): Evrysdi (risdiplam)<https:\/\/www.ema.europa.eu\/en\/documents\/smop\u2010initial\/chmp\u2010summary\u2010positive\u2010opinion\u2010evrysdi_en.pdf> (2021). Accessed June 2021."},{"key":"e_1_2_11_9_1","unstructured":"Center for Drug Evaluation and Research US Food and Drug Administration.Application Number: 213535Orig1s000 Clinical Pharmacology Review(s)\u2014 risdiplam <https:\/\/www.accessdatafdagov\/drugsatfda_docs\/nda\/2020\/213535Orig1s000ClinPharmR.pdf> (2020). 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