{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T08:52:45Z","timestamp":1786092765026,"version":"3.56.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1013509","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T00:00:00Z","timestamp":1759708800000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Drug effects are difficult to investigate in detail <jats:italic>in vivo<\/jats:italic>. However, a mechanistic understanding of drug action is clearly beneficial for both pharmaceutical development as well as for optimization of treatment designs. We here established a quantitative systems pharmacology (QSP) mouse model which simultaneously describes whole-body pharmacokinetics of murine IFN-\u03b1 as well as the cellular pharmacodynamic effect through the antiviral response biomarker Mx2. To this end, a dynamic model of intracellular IFN-\u03b1 signalling in the JAK\/STAT pathway was combined with a whole-body physiologically-based pharmacokinetic model of IFN-\u03b1 in mice. The pharmacodynamic behaviour of the resulting mouse IFN-\u03b1 QSP model was first compared to a cellular model of the JAK\/STAT pathway to compare <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> drug effects and to identify functional differences. It was found that the <jats:italic>in vitro<\/jats:italic> drug effect in the cellular model overestimates the <jats:italic>in vivo<\/jats:italic> response in mice at least by a factor of two which is partly due to the missing drug clearance <jats:italic>in vitro<\/jats:italic>. Also, the drug responses in the <jats:italic>in vitro<\/jats:italic> model were time delayed. Interspecies analyses in murine and a previously published human QSP model of IFN-\u03b1 next show a similar dynamic behavior. However, our models demonstrate eight to 16-fold stronger response levels in mice than in humans due to more efficient interferon binding. Our analysis supports a mechanistic analysis of both upstream pharmacokinetic as well as downstream pharmacodynamic drug effects through the combination of physiological knowledge and quantitative computational models. The study hence shows potential applications for QSP modelling in terms of study planning, for example by choosing physiologically relevant in vitro concentrations. Also, the QSP model allows inter-species comparisons of the effect strength in specific functional readouts, which in humans are otherwise not possible due to the limited sampling possibilities. We expect QSP modelling to play an increasingly important role in drug development and research in the future.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013509","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T17:47:03Z","timestamp":1758822423000},"page":"e1013509","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["A comparative computational analysis of IFN-alpha pharmacokinetics and its induced cellular response in mice and humans"],"prefix":"10.1371","volume":"21","author":[{"given":"Priyata","family":"Kalra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastian","family":"Kister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebekka","family":"Fendt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"K\u00f6ster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Pulverer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Sahle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8741-7786","authenticated-orcid":true,"given":"Lars","family":"Kuepfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Kummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"issue":"9","key":"pcbi.1013509.ref001","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S1359-6446(00)01540-3","article-title":"ADME\/PK as part of a rational approach to drug discovery","volume":"5","author":"P Eddershaw","year":"2000","journal-title":"Drug Discov Today"},{"issue":"1","key":"pcbi.1013509.ref002","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1002\/jps.1167","article-title":"Pharmacokinetic\/pharmacodynamic studies in drug product development","volume":"91","author":"B Meibohm","year":"2002","journal-title":"J Pharm Sci"},{"issue":"10","key":"pcbi.1013509.ref003","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1002\/psp4.12134","article-title":"Applied concepts in PBPK modeling: how to build a PBPK\/PD model","volume":"5","author":"L Kuepfer","year":"2016","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"issue":"2","key":"pcbi.1013509.ref004","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s10928-017-9559-4","article-title":"A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim","volume":"45","author":"C Niederalt","year":"2018","journal-title":"J Pharmacokinet Pharmacodyn"},{"issue":"6","key":"pcbi.1013509.ref005","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/nrd4309","article-title":"Lessons learned from the fate of AstraZeneca\u2019s drug pipeline: a five-dimensional framework","volume":"13","author":"D Cook","year":"2014","journal-title":"Nat Rev Drug Discov"},{"key":"pcbi.1013509.ref006","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ejps.2016.04.027","article-title":"Systems pharmacology - 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