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Recommendations have been made for the target\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      range of everolimus for therapeutic drug monitoring (\n                      <jats:styled-content style=\"fixed-case\">TDM<\/jats:styled-content>\n                      ) and the doses necessary to achieve this target\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A model\u2010based approach was used to predict patients' daily\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      . Time\u2010normalized\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      (\n                      <jats:styled-content style=\"fixed-case\">TN<\/jats:styled-content>\n                      \u2010\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      ) was calculated as the average predicted\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      in a time interval.\n                      <jats:styled-content style=\"fixed-case\">TN<\/jats:styled-content>\n                      \u2010\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      was used to link exposure to efficacy and safety end points via model\u2010based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure\u2010response relationship for seizure frequency (\n                      <jats:styled-content style=\"fixed-case\">SF<\/jats:styled-content>\n                      ). An extended Cox regression model was used to link exposure to the time to first adverse event.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      There was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by\n                      <jats:styled-content style=\"fixed-case\">TN<\/jats:styled-content>\n                      \u2010\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      and\n                      <jats:styled-content style=\"fixed-case\">SF<\/jats:styled-content>\n                      , regardless of patient's age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors\/inducers. Results of an extended Cox regression analyses indicated that twofold increases in\n                      <jats:styled-content style=\"fixed-case\">TN<\/jats:styled-content>\n                      \u2010\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      were not associated with statistically significant increases in the risk of stomatitis or infections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      The recommended\n                      <jats:styled-content style=\"fixed-case\">TDM<\/jats:styled-content>\n                      is to target everolimus\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>min<\/jats:sub>\n                      within a range of 5\u20107 ng\/mL initially and 5\u201015 ng\/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of\n                      <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>\n                      3A4\/P\u2010glycoprotein inducers\/inhibitors.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.14085","type":"journal-article","created":{"date-parts":[[2018,5,4]],"date-time":"2018-05-04T11:45:37Z","timestamp":1525434337000},"page":"1188-1197","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Everolimus dosing recommendations for\n                    <scp>tuberous sclerosis complex\u2013<\/scp>\n                    associated refractory seizures"],"prefix":"10.1111","volume":"59","author":[{"given":"David N.","family":"Franz","sequence":"first","affiliation":[{"name":"Department of Neurology Cincinnati Children's Hospital Medical Center Cincinnati OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Lawson","sequence":"additional","affiliation":[{"name":"Tuberous Sclerosis Multidisciplinary Management Clinic Sydney Children's Hospital Randwick New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuhal","family":"Yapici","sequence":"additional","affiliation":[{"name":"Division of Child Neurology Department of Neurology Istanbul Faculty of Medicine Istanbul University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8666-1640","authenticated-orcid":false,"given":"Christian","family":"Brandt","sequence":"additional","affiliation":[{"name":"Bethel Epilepsy Center Mara Hospital Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Kohrman","sequence":"additional","affiliation":[{"name":"NeuroDevelopmental Science Center University of Chicago Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Milh","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Service Aix\u2010Marseille University Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelheid","family":"Wiemer\u2010Kruel","sequence":"additional","affiliation":[{"name":"Epilepsy Center Kork\/TSC Center Kehl\u2010Kork Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Voi","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation East Hanover NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neva","family":"Coello","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals AG Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing","family":"Cheung","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation East Hanover NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Grosch","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals AG Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline A.","family":"French","sequence":"additional","affiliation":[{"name":"New York University Comprehensive Epilepsy Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra055323"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000254570"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02474.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)00069-1"},{"key":"e_1_2_8_6_1","first-page":"2021","article-title":"Optimal management of seizures associated with tuberous sclerosis complex: current and emerging options","volume":"10","author":"Wang S","year":"2014","journal-title":"Neuropsychiatr Dis Treat"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfv249"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70489-9"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31419-2"},{"key":"e_1_2_8_10_1","unstructured":"European Medicines Agency.Votubia everolimus.2017[cited 2017 Mar 3]. 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