{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T05:07:34Z","timestamp":1773032854465,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100006209","name":"Radboud Universitair Medisch Centrum","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006209","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Physiologically\u2010based pharmacokinetic (PBPK) models have become increasingly popular for model\u2010informed drug development (MIDD) over the past decade. While several guidelines for model evaluation exist, these are by design often of a general and non\u2010specific nature. It is clear what steps should be carried out but not necessarily how. For instance, a validation step needs to be performed to check if the predictions of a model indeed match with an external dataset. However, how to quantify this is yet unspecified. In this paper, we propose a more thorough validation approach based on the Continuous Ranked Probability Score (CRPS), a popular metric that explicitly quantifies how well a model recreates the distribution of observed data. Crucially, when applied to PBPK modeling, this metric can be used both in\u00a0situations where we have individual level predictions and in\u00a0situations where an entire virtual population is created. The CRPS can also be used to quantify the difference in predictive performance of two competing models. We applied this validation technique to compare two PBPK models. Additionally, we show that using a skill\u2010score approach facilitates the validation of a single model. While our paper focuses on PBPK models, this metric is equally applicable to other models where the goal is to create a virtual population. Additionally, we provide an easily accessible online tool that can be used to perform the proposed validation method.<\/jats:p>","DOI":"10.1002\/psp4.70175","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T10:52:06Z","timestamp":1768819926000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Validating Physiologically\u2010Based Pharmacokinetic Models Using the Continuous Ranked Probability Score: Beyond Being Correct on Average"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6964-6481","authenticated-orcid":false,"given":"Laurens","family":"Sluijterman","sequence":"first","affiliation":[{"name":"IQ Health, Section Biostatistics Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2547-9332","authenticated-orcid":false,"given":"Marjolein","family":"van Borselen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2599-7540","authenticated-orcid":false,"given":"Rick","family":"Greupink","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6127-0747","authenticated-orcid":false,"given":"Joanna","family":"IntHout","sequence":"additional","affiliation":[{"name":"IQ Health, Section Biostatistics Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12479"},{"key":"e_1_2_11_3_1","unstructured":"ASME \u201cASME V&V 40\u20132018: Assessing Credibility of Computational Modeling Through Verification and Validation: Application to Medical Devices \u201d New York: American Society of Mechanical Engineers (2018)."},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12669"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2020.01.011"},{"key":"e_1_2_11_6_1","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use \u201cGeneral Principles for Model\u2010Informed Drug Development: M15 \u201d (2024)."},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00588"},{"key":"e_1_2_11_8_1","unstructured":"Food and Drug Administration \u201cGuidance for Industry: Physiologically Based Pharmacokinetic Analyses\u2014Format and Content \u201d (2018)."},{"key":"e_1_2_11_9_1","unstructured":"European Medicines Agency \u201cGuideline on the Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation \u201d (2018)."},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12161"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600721003"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.1767"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.2133\/dmpk.24.53"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1287\/mnsc.22.10.1087"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12837"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0928-0987(02)00132-X"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-023-01326-3"},{"key":"e_1_2_11_18_1","volume-title":"Density Estimation for Statistics and Data Analysis","author":"Silverman B. 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