{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:23:23Z","timestamp":1792095803474,"version":"4.4.0"},"reference-count":51,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Foundation\u2014Flanders (FWO)","award":["G0A8119N"],"award-info":[{"award-number":["G0A8119N"]}]},{"name":"F. Hoffmann-La Roche Ltd","award":["G0A8119N"],"award-info":[{"award-number":["G0A8119N"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Tacrolimus is a crucial immunosuppressant for organ transplant patients, requiring therapeutic drug monitoring due to its variable exposure after oral intake. Physiologically based pharmacokinetic (PBPK) modelling has provided insights into tacrolimus disposition in adults but has limited application in paediatrics. This study investigated age dependency in tacrolimus exposure at the levels of absorption, metabolism, and distribution. Based on the literature data, a PBPK model was developed to predict tacrolimus exposure in adults after intravenous and oral administration. This model was then extrapolated to the paediatric population, using a unique reference dataset of kidney transplant patients. Selecting adequate ontogeny profiles for hepatic and intestinal CYP3A4 appeared critical to using the model in children. The best model performance was achieved by using the Upreti ontogeny in both the liver and intestines. To mechanistically evaluate the impact of absorption on tacrolimus exposure, biorelevant in vitro solubility and dissolution data were obtained. A relatively fast and complete release of tacrolimus from its amorphous formulation was observed when mimicking adult or paediatric dissolution conditions (dose, fluid volume). In both the adult and paediatric PBPK models, the in vitro dissolution profiles could be adequately substituted by diffusion-layer-based dissolution modelling. At the level of distribution, sensitivity analysis suggested that differences in blood plasma partitioning of tacrolimus may contribute to the variability in exposure in paediatric patients.<\/jats:p>","DOI":"10.3390\/pharmaceutics15092231","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:35:05Z","timestamp":1693298105000},"page":"2231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Investigating Tacrolimus Disposition in Paediatric Patients with a Physiologically Based Pharmacokinetic Model Incorporating CYP3A4 Ontogeny, Mechanistic Absorption and Red Blood Cell Binding"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2641-7141","authenticated-orcid":false,"given":"Matthias","family":"Van der Veken","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1478-6174","authenticated-orcid":false,"given":"Joachim","family":"Brouwers","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3120-3911","authenticated-orcid":false,"given":"Agustos Cetin","family":"Ozbey","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel, 4070 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Umehara","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel, 4070 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5203-9842","authenticated-orcid":false,"given":"Cordula","family":"Stillhart","sequence":"additional","affiliation":[{"name":"Pharmaceutical R&D, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5743-0966","authenticated-orcid":false,"given":"No\u00ebl","family":"Knops","sequence":"additional","affiliation":[{"name":"Laboratory for Pediatrics, Department of Development & Regeneration, KU Leuven, O&N3, Bus 817, 3000 Leuven, Belgium"},{"name":"Department of Pediatrics, Groene Hart Ziekenhuis, 2803 Gouda, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2595-388X","authenticated-orcid":false,"given":"Patrick","family":"Augustijns","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6821-7714","authenticated-orcid":false,"given":"Neil John","family":"Parrott","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel, 4070 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1124\/dmd.105.008680","article-title":"Effect of CYP3A5 Polymorphism on Tacrolimus Metabolic Clearance In Vitro","volume":"34","author":"Dai","year":"2006","journal-title":"Drug Metab. 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