title: Characterisation of the clinical pharmacokinetics of actinomycin D and the influence of ABCB1 pharmacogenetic variation on actinomycin D disposition in children with cancer.
abstract: OBJECTIVE
  Despite its important role in cancer treatment, there is currently very limited available information concerning the clinical pharmacology of actinomycin D (Act D). The study was designed to characterise Act D pharmacokinetics and investigate the impact of pharmacogenetic variation on Act D disposition in children with cancer.
  
  
  METHODS
  A total of 650 plasma samples collected over an 8 year period from 117 patients ≤21 years receiving Act D (0.4-1.6 mg/m(2)) were used to characterise a population pharmacokinetic model. Polymorphisms in ABCB1 were analysed in 140 patients.
  
  
  RESULTS
  A 3-compartment model provided a good fit to the data. Median values for Act D clearance and volume of distribution in the central compartment (V 1) obtained from the model were 5.3 L/h and 1.9 L (13.9 L/h/70 kg and 7.5 L/70 kg), respectively. There was substantial inter-subject variation in all pharmacokinetic parameters (coefficients of variation 53-81 % for non-normalised values). Body weight was a major determinant of Act D clearance, such that dose capping at 2 mg in larger children at a protocol dose of 1.5 mg/m(2) resulted in significantly lower area under the plasma concentration-time curves (mean AUC values: 9.3 versus 12.8 mg·min/L; P < 0.0001). No significant relationships were found between ABCB1 genetic variants and Act D pharmacokinetic parameters, nor between CL, V 1 or dose and incidence of grade 3 or 4 toxicity.
  
  
  CONCLUSIONS
  We have defined the pharmacokinetics of Act D in a paediatric patient population, providing robust estimates of key pharmacokinetic parameters. Pharmacokinetic data bring into question the current clinical practice of dose capping at 2 mg in larger patients. Pharmacogenetic variation in candidate drug transporter genes identified from preclinical studies does not significantly impact on Act D exposure in a clinical setting.
authors: Northern Institute for Cancer Research, Medical School, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors: Christopher R
authors: CR
authors: Hill
authors: Michael
authors: M
authors: Cole
authors: Julie
authors: J
authors: Errington
authors: Ghada
authors: G
authors: Malik
authors: Alan V
authors: AV
authors: Boddy
authors: Gareth J
authors: GJ
authors: Veal
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D003609:Dactinomycin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D003609:Dactinomycin