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Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and\/or mechanical ventilation during the first weeks post\u2010transplantation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense\u2010sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Disposition of tacrolimus was best characterized by a 2\u2010compartment model with clearance achieving half of the maximum elimination capacity (CL<jats:sub>MAX<\/jats:sub>\u00a0=\u00a04.1\u00a0L\/h) at 4.6\u00a0days post\u2010transplantation (T<jats:sub>50<\/jats:sub>). Compared to sedated patients, nonsedated status showed an increased first\u2010order absorption rate constant (1.1 <jats:italic>vs<\/jats:italic>. 0.1\u00a0h<jats:sup>\u22121<\/jats:sup>) and a 24% reduction in bioavailability (F<jats:sub>NS<\/jats:sub>) at 14\u2009days post\u2010transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first\u2010pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T<jats:sub>50<\/jats:sub>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post\u2010transplant time on clearance and the sedation status may be considered in routine dosing management.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15563","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T08:59:11Z","timestamp":1665565151000},"page":"1115-1126","source":"Crossref","is-referenced-by-count":4,"title":["Population pharmacokinetics of sublingually administered tacrolimus in infants and young children with liver transplantation"],"prefix":"10.1111","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8359-4040","authenticated-orcid":false,"given":"Natalia","family":"Riva","sequence":"first","affiliation":[{"name":"Unit of Innovative Treatments Hospital de Pediatr\u00eda JP Garrahan  Buenos Aires Argentina"},{"name":"National Council of Scientific and Technical Research (CONICET)  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0484-6367","authenticated-orcid":false,"given":"Manuel","family":"Ibarra","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Faculty of Chemistry Universidad de la Rep\u00fablica  Montevideo Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zinnia P.","family":"Parra\u2010Guillen","sequence":"additional","affiliation":[{"name":"Pharmacometrics &amp; Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition University of Navarra, and IdiSNA, Navarra Institute for Health Research  Pamplona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Eugenia","family":"Galv\u00e1n","sequence":"additional","affiliation":[{"name":"Intensive Care Unit Hospital de Pediatr\u00eda JP Garrahan  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Pharmacy Unit Hospital de Pediatr\u00eda JP Garrahan  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Trezeguet Renatti","sequence":"additional","affiliation":[{"name":"Unit of Innovative Treatments Hospital de Pediatr\u00eda JP Garrahan  Buenos Aires Argentina"},{"name":"National Council of Scientific and Technical Research (CONICET)  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulo","family":"C\u00e1ceres Guido","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and Clinical Pharmacology Research Unit, Pharmacy Hospital de Pediatr\u00eda JP Garrahan  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clarisa","family":"Lopez","sequence":"additional","affiliation":[{"name":"Division of Kinesiology Hospital de Pediatr\u00eda Juan P. 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