title: First report of imatinib measurement in hair: Method development and preliminary evaluation of the relation between hair and plasma concentrations with therapeutic response in chronic myeloid leukemia.
abstract: BACKGROUND
  Imatinib (IM) is a first choice drug for treatment of chronic myeloid leukemia (CML), with a widely accepted concentration threshold of 1000ng/ml being used as a target for therapeutic drug monitoring. Once adherence to the pharmacotherapeutic regimen is of paramount importance during the long treatment course of CML, the measurement of hair IM concentrations could be a surrogate of the patient's exposure to the drug.
  
  
  METHODS
  IM was extracted from a 5mg hair sample by a liquid-liquid extraction with ethyl acetate, and IM-d8 was used as internal standard (IS). After evaporation, and reconstitution in acetonitrile, the extract was injected into a LC-MS/MS system. Compounds were eluted on a C8 column in isocratic mode. IM and IS were identified in positive electrospray ionization mode using ion transitions of m/z 494.5>394.5 and 503.0>394.3 respectively. The method was applied to 102 paired hair and samples obtained from CML patients. Treatment response was evaluated according to the European LeukemiaNet recommendations.
  
  
  RESULTS
  The assay was validated in the concentration range of 0.5-25ng/mg, with intra- and inter-assay imprecisions of <13.1% and <9.3%, respectively. The limits of quantification and detection were 0.5 and 0.15ng/mg, respectively. Median hair IM concentrations are significantly smaller in patients with therapeutic failure when compared with patients with partial or optimal response (4.63 vs. 7.93, p=0.040), the same trend presented by median plasma IM concentrations (629.5 vs. 1084.8, p=0.009). An IM hair concentration below 5.8ng/mg has 83% sensibility and 70% specificity to identify patients with therapeutic failure.
  
  
  CONCLUSIONS
  A fast, sensitive, and selective LC-MS/MS method allowing quantification of IM in hair samples was developed and validated. CML patients with therapeutic failure had significantly lower hair IM concentrations when compared with patients with optimal response. These preliminary findings may support the use of hair as a matrix for IM monitoring in clinical settings, with significant logistic advantages over the collection of venous blood, particularly in developing countries.
authors.affiliation: Clinical Chemistry Department, Cliniques Universitaires St Luc, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Capron
authors.affiliation: Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brazil.
authors.forename: Marina Venzon
authors.initials: MV
authors.lastname: Antunes
authors.affiliation: Departamento de Métodos Diagnósticos, Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.
authors.forename: Sandrine Comparsi
authors.initials: SC
authors.lastname: Wagner
authors.affiliation: Departamento de Métodos Diagnósticos, Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.
authors.forename: Vanessa Suñe
authors.initials: VS
authors.lastname: Mattevi
authors.affiliation: Departamento de Métodos Diagnósticos, Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.
authors.forename: Natalia
authors.initials: N
authors.lastname: Vieira
authors.affiliation: Departamento de Métodos Diagnósticos, Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Leite
authors.affiliation: Departamento de Métodos Diagnósticos, Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Reginato
authors.affiliation: Serviço de Hematologia, Hospital Nossa Senhora da Conceição, Porto Alegre, RS, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Capra
authors.affiliation: Serviço de Hematologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Laura
authors.initials: L
authors.lastname: Fogliatto
authors.affiliation: Clinical Chemistry Department, Cliniques Universitaires St Luc, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
authors.affiliation: Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brazil. Electronic address: rafael.linden@feevale.br.
authors.forename: Rafael
authors.initials: R
authors.lastname: Linden
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000032:analysis* / Q000097:blood / Q000627:therapeutic use*; D019963:Clinical Chemistry Tests / Q000379:methods*; D005260:Female; D006197:Hair / Q000737:chemistry*; D006801:Humans; D000068877:Imatinib Mesylate / Q000032:analysis* / Q000097:blood / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate
keywords: Adherence evaluation; Chronic myeloid leukemia; Hair analysis; Imatinib; Liquid chromatography–mass spectrometry; Therapeutic drug monitoring