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Pharmacological effects are, in turn, strongly connected to the pharmacokinetic and pharmacodynamic properties of a drug, which can be characterized and investigated using pharmacometric models. Recently, the use of pharmacometrics has been proposed to provide pharmacological substantiation of pharmacoepidemiological findings derived from real\u2010world data. However, validated frameworks suggesting how to combine these two disciplines for the aforementioned purpose are missing. Therefore, we propose PHARMACOM\u2010EPI, a framework that provides a structured approach on how to identify, characterize, and apply pharmacometric models with practical details on how to choose software, format dataset, handle missing covariates\/dosing data, how to perform the external evaluation of pharmacometric models in real\u2010world data, and how to provide pharmacological substantiation of pharmacoepidemiological findings. PHARMACOM\u2010EPI was tested in a proof\u2010of\u2010concept study to pharmacologically substantiate death associated with valproate use in the Danish population aged \u2265\u00a065\u00a0years. Pharmacological substantiation of death during a follow\u2010up period of 1\u00a0year showed that in all individuals who died (<jats:italic>n<\/jats:italic>\u00a0=\u00a0169) individual predictions were within the subtherapeutic range compared with 52.8% of those who did not die (<jats:italic>n<\/jats:italic>\u00a0=\u00a01,084). Of individuals who died, 66.3% (<jats:italic>n<\/jats:italic>\u00a0=\u00a0112) had a cause of death possibly related to valproate and 33.7% (<jats:italic>n<\/jats:italic>\u00a0=\u00a057) with well\u2010defined cause of death unlikely related to valproate. This proof\u2010of\u2010concept study showed that PHARMACOM\u2010EPI was able to provide pharmacological substantiation for death associated with valproate use in the study population.<\/jats:p>","DOI":"10.1002\/cpt.2502","type":"journal-article","created":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T16:03:57Z","timestamp":1638547437000},"page":"840-856","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The PHARMACOM\u2010EPI Framework for Integrating Pharmacometric Modelling Into Pharmacoepidemiological Research Using Real\u2010World Data: Application to Assess Death Associated With Valproate"],"prefix":"10.1111","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6475-7801","authenticated-orcid":false,"given":"Hiie","family":"Soeorg","sequence":"first","affiliation":[{"name":"Department of Drug Design and Pharmacology Pharmacovigilance Research Center University of Copenhagen Copenhagen Denmark"},{"name":"Department of Drug Design and Pharmacology Pharmacometrics Research Group University of Copenhagen Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Sverrisd\u00f3ttir","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology Pharmacometrics Research Group University of Copenhagen Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7029-2860","authenticated-orcid":false,"given":"Morten","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology Pharmacovigilance Research Center University of Copenhagen Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8598-2880","authenticated-orcid":false,"given":"Trine Meldgaard","family":"Lund","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology Pharmacometrics Research Group University of Copenhagen Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0874-4744","authenticated-orcid":false,"given":"Maurizio","family":"Sessa","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology Pharmacovigilance Research Center University of Copenhagen Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,12,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2020.1780208"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12425"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e3181a663cc"},{"key":"e_1_2_7_5_1","unstructured":"U. 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