title: Evaluation of 5-fluorouracil pharmacokinetics in cancer patients with a c.1905+1G>A mutation in DPYD by means of a Bayesian limited sampling strategy.
abstract: OBJECTIVE
  Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. So far, only very limited information is available regarding the pharmacokinetics of 5FU in patients with a (partial) DPD deficiency and no limited sampling models have been developed taking into account the non-linear pharmacokinetic behaviour of 5FU. The aim of this study was to evaluate the pharmacokinetics of 5FU and to develop a limited sampling strategy to detect decreased 5FU elimination in patients with a c.1905+1G>A-related DPD deficiency.
  
  
  METHODS
  Thirty patients, heterozygous for the c.1905+1G>A mutation in DPYD, and 18 control patients received a dose of 5FU 300 mg/m2 and/or 5FU 450 mg/m2, followed by pharmacokinetic analysis of the 5FU plasma levels. A population pharmacokinetic analysis was performed in order to develop a compartmental pharmacokinetic model suitable for a limited sampling strategy. Clinical aspects of treating DPD-deficient patients with 5FU-based chemotherapy were assessed from the retrospectively collected clinical data.
  
  
  RESULTS
  In a two-compartment model with Michaelis-Menten elimination, the mean maximum enzymatic conversion capacity (V(max)) value was 40% lower in DPD-deficient patients compared with controls (p < 0.001). Using a limited sampling strategy, with V(max) values calculated from 5FU concentrations at 30 or 60 minutes, significant differences were observed between DPD-deficient patients and controls at both dose levels (p < 0.001). The positive predictive value and negative predictive value for V(max), calculated from 5FU levels at 60 minutes, were 96% and 88%, respectively, in patients treated with a single dose of 5FU 300 mg/m2. All seven DPD-deficient patients (two males and five females) who had been genotyped prior to initiation of standard 5FU-containing chemotherapy developed grade 3-4 toxicity, with one case of lethal toxicity in a female patient. No grade 4 toxicity or lethal outcome was observed in 13 DPD-deficient patients treated with reduced doses of 5FU. The average dose of 5FU in DPD-deficient patients with mild toxicity (grade ≤2) was 61 ± 16% of the normal 5FU dose (n = 10).
  
  
  CONCLUSIONS
  Profound differences in the elimination of 5FU could be detected between DPD-deficient patients and control patients. Pharmacokinetic 5FU profiling, using a single 5FU concentration at 60 minutes, may be useful for identification of DPD-deficient patients in order to reduce severe toxicity. Furthermore, treatment of DPD-deficient patients with standard 5FU-containing chemotherapy was associated with severe (lethal) toxicity.
authors.affiliation: Academic Medical Center, University of Amsterdam, Emma Childrens Hospital and Department of Clinical Chemistry, Amsterdam, the Netherlands.a.b.vankuilenburg@amc.uva.nl
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Peter
authors.initials: P
authors.lastname: Häusler
authors.forename: Andreas
authors.initials: A
authors.lastname: Schalhorn
authors.forename: Michael W T
authors.initials: MW
authors.lastname: Tanck
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Proost
authors.forename: Christoph
authors.initials: C
authors.lastname: Terborg
authors.forename: Detlev
authors.initials: D
authors.lastname: Behnke
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schwabe
authors.forename: Kati
authors.initials: K
authors.lastname: Jabschinsky
authors.forename: Jan Gerard
authors.initials: JG
authors.lastname: Maring
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D001711:Biotransformation; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006579:Heterozygote; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D009426:Netherlands; D010597:Pharmacogenetics; D010641:Phenotype; D012372:ROC Curve; D012189:Retrospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil