{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T13:12:52Z","timestamp":1783861972848,"version":"3.55.0"},"reference-count":18,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,2]],"date-time":"2025-03-02T00:00:00Z","timestamp":1740873600000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>In March 2024, ponatinib received accelerated FDA approval for the treatment of newly diagnosed Philadelphia chromosome\u2010positive acute lymphoblastic leukemia (Ph\u2009+\u2009ALL) in combination with chemotherapy based on the Phase 3 PhALLCON study (NCT03589326), which demonstrated a higher rate of minimal residual disease (MRD)\u2010negative complete remission (CR) at the end of induction (EOI) with ponatinib (34.4%) versus imatinib (16.7%; <jats:italic>p<\/jats:italic>\u2009=\u20090.002). Patients received ponatinib (30\u2009mg QD with reduction to 15\u2009mg QD upon achievement of MRD\u2010negative CR at EOI) or imatinib (600\u2009mg QD) combined with 20\u2009cycles of reduced\u2010intensity chemotherapy (induction: 3\u2009cycles; consolidation: 6\u2009cycles; and maintenance: 11\u2009cycles). Ponatinib pharmacokinetics (PK) were similar in patients in PhALLCON and patients in a previous population PK analysis. Bayesian re\u2010estimation of the previously developed population PK model adequately described PhALLCON PK data. Exposure\u2013efficacy analyses did not identify a significant relationship between ponatinib exposure and the probability of MRD\u2010negative CR at EOI (<jats:italic>p<\/jats:italic>\u2009=\u20090.619), suggesting a consistent efficacy benefit across exposures. Ponatinib exposure was not a significant predictor of arterial occlusive events, venous thromboembolic events, thrombocytopenia, or lipase increase (<jats:italic>p<\/jats:italic>\u2009&gt;\u20090.05). However, higher exposures were associated with a higher probability of hypertension (<jats:italic>p<\/jats:italic>\u2009=\u20090.0340) and alanine aminotransferase (ALT) increase (<jats:italic>p<\/jats:italic>\u2009=\u20090.0034). Dose reduction from 30 to 15\u2009mg was predicted to decrease the odds of experiencing hypertension by 37.7% and ALT increase by 44.2%. Collectively, exposure\u2013response analyses support a favorable benefit\u2013risk profile of the approved ponatinib dosage (30\u2009mg QD reduced to 15\u2009mg QD upon achievement of MRD\u2010negative CR at EOI), combined with chemotherapy, for frontline treatment of Ph\u2009+\u2009ALL.<\/jats:p>","DOI":"10.1111\/cts.70175","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T03:34:13Z","timestamp":1741059253000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Population Pharmacokinetic and Exposure\u2013Response Analyses for Ponatinib in the Phase 3 PhALLCON Study"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9266-2797","authenticated-orcid":false,"given":"Michael J.","family":"Hanley","sequence":"first","affiliation":[{"name":"Takeda Development Center Americas, Inc.  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