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As TSC\u2010associated seizures can also affect children aged between 6\u00a0months and 2\u00a0years, a modeling and simulation (M&amp;S) approach was undertaken to extrapolate exposure (trough plasma concentration (C<jats:sub>min<\/jats:sub>)) after a dose of 6\u00a0mg\/m<jats:sup>2<\/jats:sup> and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp was developed to predict C<jats:sub>min<\/jats:sub> in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short\u2010term and long\u2010term efficacy in adults (for validation) and in children, respectively. Based on the results of the M&amp;S study, everolimus at the dose of 6\u00a0mg\/m<jats:sup>2<\/jats:sup> is anticipated to be an efficacious treatment in children 6\u00a0months to 2\u00a0years of age (up to 77.8% RSF) with concentrations within the recommended target range.<\/jats:p>","DOI":"10.1002\/psp4.12502","type":"journal-article","created":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T19:49:35Z","timestamp":1583783375000},"page":"230-237","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Model\u2010Informed Drug Development for Everolimus Dosing Selection in Pediatric Infant Patients"],"prefix":"10.1002","volume":"9","author":[{"given":"Francois Pierre","family":"Combes","sequence":"first","affiliation":[{"name":"Novartis Pharmaceuticals Corporation East Hanover New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi J.","family":"Einolf","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation East Hanover New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neva","family":"Coello","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tycho","family":"Heimbach","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation East Hanover New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Handan","family":"He","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation East Hanover New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Grosch","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,4,5]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra055323"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13050"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2012.05.004"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02474.x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-13-0212"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31419-2"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61134-9"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180939"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425250802691074"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.585"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200645090-00005"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfy132"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0158476"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-015-0328-5"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.056929"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12211"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.105.005611"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.409"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1516"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-018-9600-2"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.33"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9592.2010.03323.x"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.4103\/2319-4170.110365"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-016-0708-8"}],"container-title":["CPT: Pharmacometrics &amp; 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