title: Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.
abstract: OBJECTIVE
  This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM).
  
  
  METHODS
  Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395).
  
  
  RESULTS
  Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml).
  
  
  CONCLUSIONS
  This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.
authors.affiliation: Division of Clinical Pharmacology, Service of Biomedicine, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Bugnon 17-1, 1011, Lausanne, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Gotta
authors.forename: N
authors.initials: N
authors.lastname: Widmer
authors.forename: L A
authors.initials: LA
authors.lastname: Decosterd
authors.forename: Y
authors.initials: Y
authors.lastname: Chalandon
authors.forename: D
authors.initials: D
authors.lastname: Heim
authors.forename: M
authors.initials: M
authors.lastname: Gregor
authors.forename: R
authors.initials: R
authors.lastname: Benz
authors.forename: L
authors.initials: L
authors.lastname: Leoncini-Franscini
authors.forename: G M
authors.initials: GM
authors.lastname: Baerlocher
authors.forename: M A
authors.initials: MA
authors.lastname: Duchosal
authors.forename: C
authors.initials: C
authors.lastname: Csajka
authors.forename: T
authors.initials: T
authors.lastname: Buclin
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D057285:Precision Medicine / Q000379:methods; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate