title: Tacrolimus dose requirements in paediatric renal allograft recipients are characterized by a biphasic course determined by age and bone maturation.
abstract: Despite longstanding recognition of significant age-dependent 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-term follow-up in children on tacrolimus.
  
  
  
  This was a cohort study in a tertiary hospital with standardized annual pharmacokinetic (PK) follow-up (AUC0-12hr) in recipients of a renal allograft (≤19 years), between 1998 and 2015. In addition, the presence of relevant pharmacogenetic variants was determined. The evolution of dose-corrected exposure was evaluated using mixed models.
  
  
  
  A total of 184 PK visits by 43 children were included in the study (median age: 14.6). AUC0-12hcorrected for dose per kg demonstrated a biphasic course: annual increase 4.4% (CI: 0.3-8.7%) until ±14 years of age, followed by 13.4% increase (CI 8.7-18.3%). Moreover, exposure corrected for dose per m2proved stable until 14 years (+0.8% annually; CI: -3.0 to +4.8%), followed by a steep increase ≥14 years (+11%; CI: 7.0-16.0%). Analysis according to bone maturation instead of age demonstrated a similar course with a distinct divergence at TW2: 800 (P = 0.01). Genetic variation in CYP3A4, CYP3A5, and CYP3A7 was associated with altered dose requirements, independent of age.
  
  
  
  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: ±14 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.
authors.affiliation: Dept. of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.|Laboratory for Pediatrics, Dept. of Development & Regeneration, KU Leuven, O&N3, bus 817, Leuven, Belgium.
authors.forename: Noël
authors.initials: N
authors.lastname: Knops
authors.affiliation: Dept. of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.
authors.forename: Jean
authors.initials: J
authors.lastname: Herman
authors.affiliation: Dept. of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: van Dyck
authors.affiliation: Laboratory for Pediatrics, Dept. of Development & Regeneration, KU Leuven, O&N3, bus 817, Leuven, Belgium.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Ramazani
authors.affiliation: Dept. of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.
authors.forename: Edward
authors.initials: E
authors.lastname: Debbaut
authors.affiliation: Dept. of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.
authors.forename: Rita
authors.initials: R
authors.lastname: van Damme-Lombaerts
authors.affiliation: Dept. of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.|Laboratory for Pediatrics, Dept. of Development & Regeneration, KU Leuven, O&N3, bus 817, Leuven, Belgium.
authors.forename: Elena
authors.initials: E
authors.lastname: Levtchenko
authors.affiliation: Laboratory for Pediatrics, Dept. of Development & Regeneration, KU Leuven, O&N3, bus 817, Leuven, Belgium.
authors.forename: Lambertus P
authors.initials: LP
authors.lastname: van den Heuvel
authors.affiliation: Interuniversity Institute for Biostatistics and statistical Bioinformatics, University of Leuven, Belgium, Kapucijnenvoer 35, Leuven, Belgium.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fieuws
authors.affiliation: Dept. of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kuypers
mesh_terms: D000293:Adolescent; D000367:Age Factors; D019540:Area Under Curve; D001846:Bone Development / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D010597:Pharmacogenetics; D011627:Puberty / Q000502:physiology; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus
keywords: children; drug disposition; ontogeny; pharmacokinetics; tacrolimus