{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T09:10:13Z","timestamp":1770887413114,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008272","name":"Novartis Pharmaceuticals Corporation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>This study aims to evaluate the exposure\u2013efficacy relationship of nilotinib and longitudinal BCR::ABL1 levels in patients with newly diagnosed Philadelphia chromosome\u2013positive chronic myeloid leukaemia in chronic phase (CML\u2010CP) and those who are imatinib\u2010resistant or intolerant using a semimechanistic disease model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The analysis included 489 CML\u2010CP patients from 3 nilotinib trials (NCT00109707; NCT00471497; NCT01043874) with duration of follow\u2010up ranging from 2 to 9\u00a0years. The semimechanistic disease model of CML\u2010CP consisted of quiescent leukaemic stem cells, proliferating drug\u2010susceptible and \u2010resistant bone marrow cells. Drug effect on the elimination of susceptible cells was characterized by a maximum response model based on the individual daily area under the concentration\u2013time curve over the last 24\u2009h simulated using their empirical Bayes estimates from a population pharmacokinetic model. The influence of line of therapy was evaluated on model parameters and its impact was investigated through simulations of the major molecular response (MMR) rate, defined as the proportion of the simulated profiles that achieved BCR::ABL1 level of \u22640.1% at 48 and 96\u2009weeks of treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The final disease model was based on a truncated 3\u2010year data that characterized the biphasic pattern of BCR::ABL1 transcript profiles. Line of therapy was a significant covariate of the drug kill effect, susceptible and resistant cells. Simulations of BCR::ABL1 time course predicted MMR rates at 48\u2009weeks and 96\u2009weeks for both nilotinib 300 and 400\u2009mg twice\u2010daily of 66\u201371 and 77\u201382% in first\u2010line, and 34\u201339 and 46\u201354% in second\u2010line, respectively. Results are consistent with observed MMR rates in the respective trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The ability to distinguish molecular response between lines of therapy is demonstrated using model\u2010based analysis. These nilotinib information enable the extrapolation of novel tyrosine kinase inhibitors (e.g., asciminib) response to other lines of therapy in patients with CML\u2010CP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bcp.16381","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T22:23:25Z","timestamp":1735597405000},"page":"1419-1430","source":"Crossref","is-referenced-by-count":2,"title":["Population modelling of nilotinib exposure\n                    <i>vs<\/i>\n                    . longitudinal BCR::ABL1 response in patients with chronic phase chronic myeloid leukaemia using a semimechanistic disease model"],"prefix":"10.1111","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6405-9130","authenticated-orcid":false,"given":"Sherwin K. 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