title: Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma.
abstract: BACKGROUND
  Variation in cyclophosphamide pharmacokinetics and metabolism has been highlighted as a factor that may impact on clinical outcome in various tumour types. The current study in children with B-cell non-Hodgkin's lymphoma (NHL) was designed to corroborate previous findings in a large prospective study incorporating genotype for common polymorphisms known to influence cyclophosphamide pharmacology.
  
  
  METHODS
  A total of 644 plasma samples collected over a 5 year period, from 49 B-cell NHL patients ≤ 18 years receiving cyclophosphamide (250 mg/m(2)), were used to characterise a population pharmacokinetic model. Polymorphisms in genes including CYP2B6 and CYP2C19 were analysed.
  
  
  RESULTS
  A two-compartment model provided the best fit of the population analysis. The mean cyclophosphamide clearance value following dose 1 was significantly lower than following dose 5 (1.83 ± 1.07 versus 3.68 ± 1.43 L/h/m(2), respectively; mean ± standard deviation from empirical Bayes estimates; P < 0.001). The presence of at least one CYP2B6*6 variant allele was associated with a lower cyclophosphamide clearance following both dose 1 (1.54 ± 0.11 L/h/m(2) versus 2.20 ± 0.31 L/h/m(2), P = 0.033) and dose 5 (3.12 ± 0.17 L/h/m(2) versus 4.35 ± 0.37 L/h/m(2), P = 0.0028), as compared to homozygous wild-type patients. No pharmacokinetic parameters investigated were shown to have a significant influence on progression free survival.
  
  
  CONCLUSIONS
  The results do not support previous findings of a link between cyclophosphamide pharmacokinetics or metabolism and disease recurrence in childhood B-cell NHL. While CYP2B6 genotype was shown to influence pharmacokinetics, there was no clear impact on clinical outcome.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: G.J.Veal@ncl.ac.uk.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Health and Society, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Cole
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Tata Memorial Hospital, Mumbai, India.
authors.forename: Girish
authors.initials: G
authors.lastname: Chinnaswamy
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Julieann
authors.initials: J
authors.lastname: Sludden
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Jamieson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Errington
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Ghada
authors.initials: G
authors.lastname: Malik
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Hill
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Chamberlain
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
mesh_terms: D000293:Adolescent; D000367:Age Factors; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008954:Models, Biological; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6
keywords: B-cell NHL; Chemotherapy; Cyclophosphamide; Paediatrics; Pharmacogenetics; Pharmacokinetics