title: A pharmacogenetic predictive model for paclitaxel clearance based on the DMET platform.
abstract: OBJECTIVE
  Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug-metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes.
  
  
  METHODS
  In 270 paclitaxel-treated patients, unbound plasma concentrations were determined and pharmacokinetic parameters were estimated from a previously developed population pharmacokinetic model (NONMEM). Patients were divided into a training- and validation set. Genetic variants determined by the DMET platform were selected from the training set to be included in the prediction model when they were associated with low paclitaxel clearance (1 SD below mean clearance) and subsequently tested in the validation set.
  
  
  RESULTS
  A genetic prediction model including 14 single-nucleotide polymorphisms (SNP) was developed on the training set. In the validation set, this model yielded a sensitivity of 95%, identifying most patients with low paclitaxel clearance correctly. The positive predictive value of the model was only 22%. The model remained associated with low clearance after multivariate analysis, correcting for age, gender, and hemoglobin levels at baseline (P = 0.02).
  
  
  CONCLUSIONS
  In this first large-sized application of the DMET-platform for paclitaxel, we identified a 14 SNP model with high sensitivity to identify patients with low paclitaxel clearance. However, due to the low positive predictive value we conclude that genetic variability encoded in the DMET-chip alone does not sufficiently explain paclitaxel clearance.
authors.affiliation: Authors' Affiliations: Departments of Medical Oncology, Clinical Chemistry, and Trials and Statistics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Anne-Joy M
authors.initials: AJ
authors.lastname: de Graan
authors.forename: Laure
authors.initials: L
authors.lastname: Elens
authors.forename: Marcel
authors.initials: M
authors.lastname: Smid
authors.forename: John W
authors.initials: JW
authors.lastname: Martens
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Annemieke J M
authors.initials: AJ
authors.lastname: Nieuweboer
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.forename: Samira
authors.initials: S
authors.lastname: Elbouazzaoui
authors.forename: Erik A C
authors.initials: EA
authors.lastname: Wiemer
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D015233:Models, Statistical; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D055815:Young Adult
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D026901:Membrane Transport Proteins; D017239:Paclitaxel