title: Should therapeutic drug monitoring of the unbound fraction of imatinib and its main active metabolite N-desmethyl-imatinib be developed?
abstract: OBJECTIVE
  The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both imatinib and its main active metabolite (N-desmethyl-imatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations.
  
  
  METHODS
  The quantification of unbound fraction of imatinib and N-desmethyl-imatinib was performed using plasma ultrafiltration coupled with LC-MS/MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients.
  
  
  RESULTS
  The mean unbound fractions of imatinib and N-desmethyl-imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for imatinib and 34 % for N-desmethyl-imatinib. No correlation was observed between these measured individual imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-imatinib/imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with inter-individual variabilities of 71 and 86 %, respectively.
  
  
  CONCLUSIONS
  The large inter-individual variability for the unbound fraction of both imatinib and N-desmethyl-imatinib warrants further evaluation of the pharmacokinetic-pharmacodynamic relationship as a potential relevant marker of imatinib therapeutic outcomes.
authors.affiliation: EA4553 Laboratoire de Pharmacocinétique, Institut Claudius-Regaud, Université de Toulouse, 31052 Toulouse, France.
authors.forename: Peggy
authors.initials: P
authors.lastname: Gandia
authors.forename: Cécile
authors.initials: C
authors.lastname: Arellano
authors.forename: Thierry
authors.initials: T
authors.lastname: Lafont
authors.forename: Françoise
authors.initials: F
authors.lastname: Huguet
authors.forename: Laurence
authors.initials: L
authors.lastname: Malard
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000378:metabolism*; D001549:Benzamides; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism*; D011485:Protein Binding; D011743:Pyrimidines / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009961:Orosomucoid; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate