{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:26:04Z","timestamp":1787199964185,"version":"build-2736575974"},"reference-count":51,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Model\u2010informed precision dosing is often constrained by the limited generalizability of traditional population pharmacokinetic models, especially in critically ill patients. A hybrid machine learning\u2010population pharmacokinetic framework is proposed to improve a priori pharmacokinetic predictions by integrating real\u2010world clinical data. This approach was applied to vancomycin trough concentration prediction. Two widely used two\u2010compartment population pharmacokinetic models provided individual pharmacokinetic parameter estimates. Maximum a posteriori Bayesian estimation was used to adjust population parameters for individual patients based on drug administration records, therapeutic drug monitoring values, and patient\u2010specific covariates from the MIMIC\u2010IV database. The resulting clearance and central volume of distribution estimates served as training targets for XGBoost and symbolic regression models. Machine learning\u2010predicted parameters were reinserted into the original pharmacokinetic equations to generate a priori vancomycin trough concentrations without reliance on therapeutic drug monitoring input. The hybrid models demonstrated improved prediction accuracy over traditional population pharmacokinetic covariate models and reduced vancomycin trough concentration prediction error by up to ~20%. XGBoost generally provided the highest predictive performance, while symbolic regression produced interpretable mathematical expressions revealing associations between non\u2010traditional clinical predictors and pharmacokinetic parameters, highlighting a trade\u2010off between accuracy and interpretability. This framework illustrates the potential of combining machine learning with population pharmacokinetic modeling to refine pharmacokinetic parameter estimation and support more precise, individualized dosing. The workflow is adaptable to other drugs and patient populations, offering a generalizable methodological strategy to identify non\u2010traditional predictors and enhance existing pharmacometric model performance in real\u2010world clinical settings.<\/jats:p>","DOI":"10.1002\/psp4.70313","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:25:09Z","timestamp":1785839109000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Traditional Covariates: An Interpretable Machine Learning Workflow for Improved Hybrid Pharmacometric Modeling"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1826-6063","authenticated-orcid":false,"given":"Freek J. A.","family":"Relouw","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Eindhoven University of Technology  Eindhoven the Netherlands"},{"name":"Department of Hospital Pharmacy Erasmus University Medical Center  Rotterdam the Netherlands"},{"name":"Rotterdam Clinical Pharmacometrics Group  Rotterdam the Netherlands"},{"name":"Division of Neonatology, Department of Neonatal &amp; Pediatric ICU Erasmus MC  Rotterdam the Netherlands"},{"name":"Department of Intensive Care Medicine Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0159-175X","authenticated-orcid":false,"given":"Jort J. M. T.","family":"Lokers","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Eindhoven University of Technology  Eindhoven the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6953-0358","authenticated-orcid":false,"given":"Tim","family":"Preijers","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Erasmus University Medical Center  Rotterdam the Netherlands"},{"name":"Rotterdam Clinical Pharmacometrics Group  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-638X","authenticated-orcid":false,"given":"Sebastiaan D. T.","family":"Sassen","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Erasmus University Medical Center  Rotterdam the Netherlands"},{"name":"Rotterdam Clinical Pharmacometrics Group  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9375-4730","authenticated-orcid":false,"given":"Natal A. W.","family":"van Riel","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Eindhoven University of Technology  Eindhoven the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1202-3643","authenticated-orcid":false,"given":"Birgit C. P.","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Erasmus University Medical Center  Rotterdam the Netherlands"},{"name":"Rotterdam Clinical Pharmacometrics Group  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12451"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13115"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2012.11.048"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00420"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/1751143714564816"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473\u20103099(14)70036\u20102"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12838"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/bf01061469"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12741"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.9979"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13306"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dmpk.2024.101004"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14091814"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ifacsc.2024.100252"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12828"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1352113"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010021\u201001033\u2010x"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010024\u201000934\u20106"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010021\u201009757\u2010w"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010023\u201009887\u20103"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010023\u201009875\u20107"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010012\u20109258\u20100"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010021\u201009782\u20109"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.176"},{"key":"e_1_2_11_26_1","unstructured":"R.Bartolucci \u201cDevelopment of a Genetic Algorithm for Covariate Analysis in Population Pharmacokinetic Models\u201d(2021) 29."},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010006\u20109004\u20106"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010021\u201009793\u20106"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.4103\/2279\u2010042X.192453"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.5935\/0103\u2010507X.20160071"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.2147\/TCRM.S266295"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/aas.12897"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41597\u2010022\u201001899\u2010x"},{"key":"e_1_2_11_34_1","unstructured":"A.Johnson L.Bulgarelli T.Pollard et\u00a0al. \u201cData from: MIMIC\u2010IV\u201d(2024) https:\/\/doi.org\/10.13026\/KPB9\u2010MT58."},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.101.23.e215"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14498"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12689"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkv372"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000490"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2019.02.029"},{"key":"e_1_2_11_41_1","doi-asserted-by":"crossref","unstructured":"T.Akiba S.Sano T.Yanase T.Ohta andM.Koyama \u201cOptuna: A Next\u2010generation Hyperparameter Optimization Framework \u201dPresented at: Proceedings of the 25th ACM SIGKDD International Conference on Knowledge Discovery & Data Mining; 2019; Anchorage AK USA https:\/\/doi.org\/10.1145\/3292500.3330701.","DOI":"10.1145\/3292500.3330701"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010009\u20109133\u20100"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12808"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00499\u201025"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12071113"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2010.03.001"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1097\/00062752\u2010200003000\u201000007"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra041809"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3203"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.i3140"},{"key":"e_1_2_11_51_1","unstructured":"S. M.LundbergandS.\u2010I.Lee \u201cA Unified Approach to Interpreting Model Predictions \u201dPresented At: Proceedings of the 31st International Conference on Neural Information Processing Systems; 2017; Long Beach California USA."},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010016\u20109492\u2010y"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70313","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.70313","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70313","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:11:04Z","timestamp":1787199064000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70313"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":51,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/psp4.70313"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70313","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2026-02-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70313"}}