title: Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1.
abstract: OBJECTIVE
  The narrow therapeutic index and large interpatient variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with neurofibromatosis type 1 (NF1). The objectives of this study were to estimate sirolimus clearance in a cohort of children with NF1 using data collected in a concentration-guided trial, to evaluate the effect of treatment duration on clearance and dose requirements, and to evaluate the association of sirolimus clearance with patient-specific factors, including age, weight, body surface area (BSA), race, and sex.
  
  
  METHODS
  Sirolimus concentration-time data were collected from an ongoing prospective trial in children with NF1. An iterative 2-stage Bayesian method was used for the PK parameter analyses.
  
  
  RESULTS
  Data from 44 patients with NF1 were included in the analyses. Mean age was 8.4 years (SD 4.5, range 3-18), and mean weight was 29.8 kg (SD 16.7, range 12-85.8). Mean sirolimus clearance was 11.8 L/h (SD 4.6, range 2.2-24.1), and the mean dose to obtain a target trough concentration of 10-15 ng/mL was 2.0 mg/m administered twice daily (SD 0.72, range 0.77-3.85). A nonlinear relationship between age and clearance was observed. Total body weight and BSA were strong predictors of sirolimus clearance (r = 0.67 and 0.65, respectively).
  
  
  CONCLUSIONS
  Sirolimus clearance in children with NF1 is comparable with that in pediatric transplant patients. Clearance was most associated with body size parameters (BSA and total body weight) in children with NF1. When normalized for size, an age effect on clearance was observed in the youngest patients, most likely because of the maturational changes in drug absorption and metabolism. A mean dose of 2.0 mg/m twice a day was required for attainment of target trough concentrations of 10-15 ng/mL in children greater than 3 years of age who have NF1. The updated model will allow PK-guided individualized dosing of sirolimus in patients with NF1.
authors.affiliation: Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Scott
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Courter
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Saldaña
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Michael
authors.initials: M
authors.lastname: Fisher
authors.forename: Brian
authors.initials: B
authors.lastname: Weiss
authors.forename: John
authors.initials: J
authors.lastname: Perentesis
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000293:Adolescent; D000367:Age Factors; D001499:Bayes Theorem; D001830:Body Surface Area; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D009456:Neurofibromatosis 1 / Q000188:drug therapy*; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus