{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T08:29:04Z","timestamp":1780734544759,"version":"3.54.1"},"reference-count":51,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,12,13]],"date-time":"2016-12-13T00:00:00Z","timestamp":1481587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Despite longstanding recognition of significant age\u2010dependent differences in drug disposition during childhood, the exact course and the underlying mechanisms are not known. Our aim was to determine the course and determinants of individual relative dose requirements, during long\u2010term follow\u2010up in children on tacrolimus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This was a cohort study in a tertiary hospital with standardized annual pharmacokinetic (PK) follow\u2010up (AUC<jats:sub>0\u201312hr<\/jats:sub>) in recipients of a renal allograft (\u226419 years), between 1998 and 2015. In addition, the presence of relevant pharmacogenetic variants was determined. The evolution of dose\u2010corrected exposure was evaluated using mixed models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 184 PK visits by 43 children were included in the study (median age: 14.6). AUC<jats:sub>0\u201312h<\/jats:sub>corrected for dose per kg demonstrated a biphasic course: annual increase 4.4% (CI: 0.3\u20138.7%) until \u00b114 years of age, followed by 13.4% increase (CI 8.7\u201318.3%). Moreover, exposure corrected for dose per m<jats:sup>2<\/jats:sup>proved stable until 14 years (+0.8% annually; CI: \u22123.0 to +4.8%), followed by a steep increase \u226514 years (+11%; CI: 7.0\u201316.0%). Analysis according to bone maturation instead of age demonstrated a similar course with a distinct divergence at TW2: 800 (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.01). Genetic variation in<jats:italic>CYP3A4<\/jats:italic>,<jats:italic>CYP3A5<\/jats:italic>, and<jats:italic>CYP3A7<\/jats:italic>was associated with altered dose requirements, independent of age.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Children exhibit a biphasic course in tacrolimus disposition characterized by a high and stable drug clearance until a specific phase in pubertal development (TW2: 800 at age: \u00b114 years), followed by an important decline in relative dose requirements thereafter. Pharmacogenetic variation demonstrated an age\/puberty independent effect. We suggest a critical reappraisal of current paediatric dosing algorithms for tacrolimus and drugs with a similar disposition.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13174","type":"journal-article","created":{"date-parts":[[2016,12,14]],"date-time":"2016-12-14T04:06:42Z","timestamp":1481688402000},"page":"863-874","source":"Crossref","is-referenced-by-count":13,"title":["Tacrolimus dose requirements in paediatric renal allograft recipients are characterized by a biphasic course determined by age and bone maturation"],"prefix":"10.1111","volume":"83","author":[{"given":"No\u00ebl","family":"Knops","sequence":"first","affiliation":[{"name":"Dept. of Pediatric Nephrology and Solid Organ Transplantation University Hospitals Leuven Herestraat 49 Leuven Belgium"},{"name":"Laboratory for Pediatrics, Dept. of Development &amp; Regeneration KU Leuven O&amp;N3, bus 817 Leuven 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