{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T01:14:08Z","timestamp":1788484448313,"version":"build-2803163510"},"reference-count":21,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["NIHR128465."],"award-info":[{"award-number":["NIHR128465."]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Imatinib improves hemodynamics in pulmonary arterial hypertension (PAH), but dose\u2010dependent toxicity has limited its clinical development. We aimed to quantify the dose\u2013efficacy\u2013toxicity relationship and evaluate alternative dosing strategies using data from the PIPAH trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analysed data from the Phase II PIPAH trial (17 enrolled; 15 contributed pharmacokinetic and safety data, 11 daily hemodynamic data). Total pulmonary resistance (TPR) was described using a turnover model and recurrent adverse events (AEs) using a repeated time\u2010to\u2010event model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Simulations showed that TPR reduction was dose\u2010dependent ( 50%;  247\u2009mg), whereas AE risk increased nonlinearly with dose ( 307\u2009mg). Although a cumulative dose of 2400\u2009mg produced similar TPR reductions, 300\u2009mg once daily achieved a 20% reduction earlier than 200\u2009mg (8\n                      <jats:italic>vs<\/jats:italic>\n                      . 12\u2009weeks) with only a modest increase in AE burden.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Simulations support initiating treatment at 200\u2009mg once daily with escalation to 300\u2009mg after 8\u201312\u2009weeks in patients who tolerate treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70806","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:51:01Z","timestamp":1788483061000},"source":"Crossref","is-referenced-by-count":0,"title":["Adaptive imatinib regimens can mitigate cumulative toxicity while sustaining hemodynamic benefit: A model\u2010based simulation of the positioning imatinib for pulmonary arterial hypertension trial"],"prefix":"10.1002","author":[{"given":"Medhat M.","family":"Said","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"de Mooij","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dian","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reitze J.","family":"Ovelgonne","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rami","family":"Biram","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Delgado\u2010SanMartin","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine Imperial College London, Hammersmith Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M. K.","family":"Rothman","sequence":"additional","affiliation":[{"name":"Division of Clinical Medicine The University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia S.","family":"Villar","sequence":"additional","affiliation":[{"name":"University of Cambridge MRC Biostatistics Unit  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5748-6978","authenticated-orcid":false,"given":"Andreas A.","family":"Roussakis","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine Imperial College London, Hammersmith Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurjan","family":"Aman","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences Amsterdam UMC, location VUmc  Amsterdam The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron A. A.","family":"Math\u00f4t","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora L.","family":"Swart","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam  Amsterdam The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R.","family":"Wilkins","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine Imperial College London, Hammersmith Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-3407","authenticated-orcid":false,"given":"Imke H.","family":"Bartelink","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacy Amsterdam UMC  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01913\u20102018"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/2045894020977300"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/jaha.121.024969"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2017.84"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010011\u20100729\u20107"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201001\u20100123oc"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.112.000765"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2015.05.025"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/pul2.12352"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/20458940211052823"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202410\u20101929oc"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102125.2012.04422.x"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12797"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010017\u20100162\u20109"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","unstructured":"WilkinsM RoussakisA Investigating the use of oral imatinib as a treatment for pulmonary arterial hypertension.2025.","DOI":"10.1186\/ISRCTN94603622"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmc051946"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003\u20104819\u2010145\u20102\u2010200607180\u201000020"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416\u2010023\u201002269\u2010z"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/20458940211057071"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2019.06.010"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12774"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70806","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bcp.70806","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bcp.70806","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:51:03Z","timestamp":1788483063000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/bcp.70806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":21,"alternative-id":["10.1002\/bcp.70806"],"URL":"https:\/\/doi.org\/10.1002\/bcp.70806","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]},"article-number":"bcp.70806"}}