title: Developmental pharmacokinetics of sirolimus: Implications for precision dosing in neonates and infants with complicated vascular anomalies.
abstract: BACKGROUND
  Sirolimus has recently been shown to be efficacious and tolerable in pediatric patients with complicated vascular anomalies. Nevertheless, dosing information remains very limited especially for neonates and infants. The purpose of this study was to develop an age-appropriate sirolimus starting dosing regimen based on the developmental changes in drug elimination capacity using data collected in neonates and infants.
  
  
  METHODS
  A recently developed sirolimus maturation model [Emoto et al. CPT Pharmacometrics Syst Pharmacol, 2016] was used to simulate clearance estimates using realistic age and weight covariates for age cohorts aged 0-24 months. Next, predose concentrations at steady state were generated for each age cohort of neonates and infants. Dose requirements to attain predefined target trough concentration ranges (10-15 and 5-10 ng/ml) were simulated across the different age groups. Starting doses were chosen to maximize the likelihood of achieving sirolimus-targeted concentrations.
  
  
  RESULTS
  The trajectory of simulated sirolimus clearances increased with age and was in agreement with the previous findings in the Phase 2 study. The proposed dosing regimens covered eight age cohorts and resulted in target attainment of more than 75-95% across selected regimens.
  
  
  CONCLUSIONS
  This study identified age-appropriate sirolimus dosing regimens for neonates and infants. The algorithm in combination with therapeutic drug management will facilitate sirolimus precision dosing in young children with vascular anomalies. A prospective evaluation is being planned.
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Chie
authors.initials: C
authors.lastname: Emoto
authors.affiliation: Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Paula S
authors.initials: PS
authors.lastname: Mobberley-Schuman
authors.affiliation: Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Hammill
authors.affiliation: Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Adams
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000465:Algorithms; D001808:Blood Vessels / Q000002:abnormalities*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008962:Models, Theoretical; D020123:Sirolimus / Q000493:pharmacokinetics*
chemical_list: D020123:Sirolimus
keywords: developmental pharmacology; mTOR inhibitor; pharmacometrics, model-based precision dosing