title: Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer.
abstract: OBJECTIVE
  Use of the anti-tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D pharmacokinetic data make it challenging to develop a sound rationale for defining dosing regimens in younger patients. The study aim was to develop a physiologically based pharmacokinetic (PBPK) model using a combination of data from the literature and generated from experimental analyses.
  
  
  METHODS
  Assays to determine actinomycin D Log P, blood:plasma partition ratio and ABCB1 kinetics were conducted. These data were combined with physiochemical properties sourced from the literature to generate a compound file for use within the modelling-simulation software Simcyp (version 14 release 1). For simulation, information was taken from two datasets, one from 117 patients under the age of 21 and one from 20 patients aged 16-48.
  
  
  RESULTS
  The final model incorporated clinical renal and biliary clearance data and an additional systemic clearance value. The mean AUC0-26h of simulated subjects was within 1.25-fold of the observed AUC0-26h (84 ng h ml(-1) simulated vs. 93 ng h ml(-1) observed). For the younger age ranges, AUC predictions were within two-fold of observed values, with simulated data from six of the eight age/dose ranges falling within 15% of observed data. Simulated values for actinomycin D AUC0-26h and clearance in infants aged 0-12 months ranged from 104 to 115 ng h ml(-1) and 3.5-3.8 l h(-1) , respectively.
  
  
  CONCLUSIONS
  The model has potential utility for prediction of actinomycin D exposure in younger patients and may help guide future dosing. However, additional independent data from neonates and infants is needed for further validation. Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Walsh
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bonner
authors.affiliation: Simcyp Limited (a Certara Company), Sheffield, UK.
authors.forename: Trevor N
authors.initials: TN
authors.lastname: Johnson
authors.affiliation: Simcyp Limited (a Certara Company), Sheffield, UK.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Neuhoff
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Essam A
authors.initials: EA
authors.lastname: Ghazaly
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW, 2006, Australia.
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003198:Computer Simulation; D003609:Dactinomycin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004285:Dogs; D005260:Female; D006801:Humans; D007223:Infant; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D003609:Dactinomycin
keywords: actinomycin D; cancer; paediatrics; pharmacokinetics; physiologically based pharmacokinetic modelling