title: Physiologically based pharmacokinetic model for 6-mercpatopurine: exploring the role of genetic polymorphism in TPMT enzyme activity.
abstract: OBJECTIVE
  To extend the physiologically based pharmacokinetic (PBPK) model developed for 6-mercaptopurine to account for intracellular metabolism and to explore the role of genetic polymorphism in the TPMT enzyme on the pharmacokinetics of 6-mercaptopurine.
  
  
  METHODS
  The developed PBPK model was extended for 6-mercaptopurine to account for intracellular metabolism and genetic polymorphism in TPMT activity. System and drug specific parameters were obtained from the literature or estimated using plasma or intracellular red blood cell concentrations of 6-mercaptopurine and its metabolites. Age-dependent changes in parameters were implemented for scaling, and variability was also introduced for simulation. The model was validated using published data.
  
  
  RESULTS
  The model was extended successfully. Parameter estimation and model predictions were satisfactory. Prediction of intracellular red blood cell concentrations of 6-thioguanine nucleotide for different TPMT phenotypes (in a clinical study that compared conventional and individualized dosing) showed results that were consistent with observed values and reported incidence of haematopoietic toxicity. Following conventional dosing, the predicted mean concentrations for homozygous and heterozygous variants, respectively, were about 10 times and two times the levels for wild-type. However, following individualized dosing, the mean concentration was around the same level for the three phenotypes despite different doses.
  
  
  CONCLUSIONS
  The developed PBPK model has been extended for 6-mercaptopurine and can be used to predict plasma 6-mercaptopurine and tissue concentration of 6-mercaptopurine, 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide in adults and children. Predictions of reported data from clinical studies showed satisfactory results. The model may help to improve 6-mercaptopurine dosing, achieve better clinical outcome and reduce toxicity.
authors.affiliation: Centre for Applied Pharmacokinetics Research, Manchester Pharmacy School, The University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Kayode
authors.initials: K
authors.lastname: Ogungbenro
authors.affiliation: Centre for Applied Pharmacokinetics Research, Manchester Pharmacy School, The University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Leon
authors.initials: L
authors.lastname: Aarons
mesh_terms: D000328:Adult; D000367:Age Factors; D002648:Child; D003198:Computer Simulation; D006801:Humans; D015122:Mercaptopurine / Q000097:blood / Q000493:pharmacokinetics*; D008780:Methyltransferases / Q000235:genetics*; D008954:Models, Biological; D019384:Nucleic Acid Synthesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase
keywords: 6-mercaptopurine; PBPK model; TPMT; acute lymphoblastic leukaemia; modelling; pharmacokinetics