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In this study, this hybrid technique is applied to the real multiobjective precision dosing problem of givinostat treatment in polycythemia vera (PV) patients. PV is a chronic myeloproliferative disease with an overproduction of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). The therapeutic goal is to simultaneously normalize the levels of these efficacy\/safety biomarkers, thus inducing a complete hematological response (CHR). An RL algorithm, Q\u2010Learning (QL), was integrated with a PK\u2010PD model describing the givinostat effect on PLT, WBC, and HCT to derive both an adaptive dosing protocol (QL<jats:sub>pop<\/jats:sub>\u2010agent) for the whole population and personalized dosing strategies by coupling a specific QL\u2010agent to each patient (QL<jats:sub>ind<\/jats:sub>\u2010agents). QL<jats:sub>pop<\/jats:sub>\u2010agent learned a general adaptive dosing protocol that achieved a similar CHR rate (77% vs. 83%) when compared to the actual givinostat clinical protocol on 10 simulated populations. Treatment efficacy and safety increased with a deeper dosing personalization by QL<jats:sub>ind<\/jats:sub>\u2010agents. These QL\u2010based patient\u2010specific adaptive dosing rules outperformed both the clinical protocol and QL<jats:sub>pop<\/jats:sub>\u2010agent by reaching the CHR in 93% of the test patients and completely avoided severe toxicities during the whole treatment period. These results confirm that RL and PK\u2010PD models can be valid tools for supporting adaptive dosing strategies as interesting performances were achieved in both learning a general set of rules and in customizing treatment for each patient.<\/jats:p>","DOI":"10.1002\/psp4.70012","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T05:15:07Z","timestamp":1746508507000},"page":"1018-1031","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Precision Dosing in Presence of Multiobjective Therapies by Integrating Reinforcement Learning and <scp>PK<\/scp>\u2010<scp>PD<\/scp> Models: Application to Givinostat Treatment of Polycythemia Vera"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-2140","authenticated-orcid":false,"given":"Alessandro","family":"De Carlo","sequence":"first","affiliation":[{"name":"Electrical, Computer and Biomedical Engineering University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9801-2135","authenticated-orcid":false,"given":"Elena Maria","family":"Tosca","sequence":"additional","affiliation":[{"name":"Electrical, Computer and Biomedical Engineering University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8931-4676","authenticated-orcid":false,"given":"Paolo","family":"Magni","sequence":"additional","affiliation":[{"name":"Electrical, Computer and Biomedical Engineering University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010pharmtox\u2010010617\u2010052446"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00420"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2018.1501271"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00177"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1933"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.1004"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1094281"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010statistics\u2010022513\u2010115553"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3904\/kjim.2009.24.1.1"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.4155\/ipk\u20102017\u20100011"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010pharmtox\u2010033020\u2010113257"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.659"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14801"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12377"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12418"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1777"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3356"},{"key":"e_1_2_9_19_1","volume-title":"Reinforcement Learning: An Introduction","author":"Sutton R. 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