title: The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation.
abstract: OBJECTIVE
  In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients.
  
  
  METHODS
  Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition.
  
  
  RESULTS
  Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p = 0.038]. In kidney but not liver transplants, CYP3A5 expressors needed significantly higher TAC doses than nonexpressors [0.15 (0.07-0.20) vs. 0.09 (0.02-0.35) mg/kg/12h, P = 0.001]. In these patients, age and CYP3A5 genotype were independently associated with TAC dosing requirement. In liver, but not kidney transplant patients, homozygous ABCB1 T-T-T haplotype carriers needed higher TAC doses than noncarriers [0.26 (0.15-0.32) vs. 0.11 (0.01-0.25) mg/kg/12h, p = 0.013].
  
  
  CONCLUSIONS
  CYP3A5 genotype may explain variation in tacrolimus disposition early after transplant in pediatric kidney recipients, independent of age-related variation. In contrast, in pediatric liver recipients, variation in tacrolimus disposition appears related to age and ABCB1 genotype. These findings illustrate the importance of the interplay among age, genotype, and transplant organ on tacrolimus disposition.
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children's Hospital, Sk3140, Dr. Molewaterplein 60, 3015 GJ, Rotterdam, The Netherlands. s.dewildt@erasmusmc.nl
authors.forename: Saskia N
authors.initials: SN
authors.lastname: de Wildt
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Offie P
authors.initials: OP
authors.lastname: Soldin
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Soldin
authors.forename: Parvaneh Yazdani
authors.initials: PY
authors.lastname: Brojeni
authors.forename: Ilse P
authors.initials: IP
authors.lastname: van der Heiden
authors.forename: Chris
authors.initials: C
authors.lastname: Parshuram
authors.forename: Irena
authors.initials: I
authors.lastname: Nulman
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D007223:Infant; D007231:Infant, Newborn; D016030:Kidney Transplantation / Q000502:physiology*; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D012720:Severity of Illness Index; D016559:Tacrolimus / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus