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As IC\n                      <jats:sub>50<\/jats:sub>\n                      is not an appropriate parameter to describe the potency of the inhibition in the presence of a covalent binding inhibitor. A BTK covalent binding model was developed using\n                      <jats:italic>k<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>inact<\/jats:italic>\n                      <\/jats:sub>\n                      <jats:italic>\/K<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>I<\/jats:italic>\n                      <\/jats:sub>\n                      as key parameter to account for covalent binding. The ibrutinib-BTK covalent binding model was used to describe the effect of daily doses of 140, 280, 420 and 560\u00a0mg on the proportion of subjects with more than 90% BTK inhibition at steady state trough concentrations. Predictive performance of the model was assessed using the available ibrutinib BTK inhibition data following QD dosing. Model-based predictions were used to identify the minimum ibrutinib QD dose that provides more than 90% inhibition in more than 90% of the subjects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The covalent binding model was able to describe the data and predicted that ibrutinib QD dose reduced from 420\u00a0mg to 280\u00a0mg or 140\u00a0mg may inhibit de novo synthetized BTK efficiently in a CLL population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Using a model-based approach showed that reducing the ibrutinib dosing regimen to 280\u00a0mg QD or even 140\u00a0mg in case of adverse events could maintain BTK inhibition over the entire dosing interval.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00280-025-04753-0","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T23:29:51Z","timestamp":1740698991000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Evaluation of Bruton\u2019s Tyrosine Kinase (BTK) inhibition with alternative doses of ibrutinib in subjects with Chronic Lymphocytic Leukemia (CLL)"],"prefix":"10.1007","volume":"95","author":[{"given":"Aziz","family":"Ouerdani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"Valenzuela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoline","family":"Treijtel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahor","family":"Haddish-Berhane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Desphande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srimathi","family":"Srinivasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Jos\u00e9","family":"Perez Ruixo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"4753_CR1","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1200\/JCO.2012.42.7906","volume":"31","author":"RH Advani","year":"2013","unstructured":"Advani RH, Buggy JJ, Sharman JP et al (2013) Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed\/refractory B-cell malignancies. 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