title: Liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of the tyrosine kinase inhibitor, midostaurin, in plasma from patients with advanced systemic mastocytosis.
abstract: We developed and validated quantitative bioanalytical liquid chromatography-tandem mass spectrometry assay for the protein kinase inhibitor, midostaurin. Plasma samples were pre-treated using a protein precipitation with methanol containing midostaurin-d5 as an internal standard. After centrifugation, 5μL of the supernatant was injected into the chromatographic system. The system consisted of a 3.5μm particle bonded octadecyl silica column, with gradient elution using a mixture of 0.1% (v/v) formic acid in acetonitrile and 10mM ammonium formate in water with 0.1% formic acid. The analyte was quantified using the selected reaction-monitoring mode of a triple quadrupole mass spectrometer equipped with a heated electrospray interface. The assay was validated in a 75-2500ng/mL calibration range. For quality control, within-day and between-day precisions were 1.2-2.8%, and 1.2-6.9%, respectively. The β-expectation tolerance limit (accuracy) met the limits of acceptance ±15% (±20% for the LLQ). The drug was sufficiently stable under all relevant analytical conditions. The assay has successfully been used to assess drug levels for therapeutic drug monitoring in patients presenting advanced systemic mastocytosis and treated with the promising midostaurin.
authors: Clinical Pharmacy, Necker Hospital, 149 rue de Sèvres, Paris 75015, France. Electronic address: philippe.bourget@nck.aphp.fr.
authors: Philippe
authors: P
authors: Bourget
authors: Clinical Pharmacy, Necker Hospital, 149 rue de Sèvres, Paris 75015, France. Electronic address: alexandre.amin@nck.aphp.fr.
authors: Alexandre
authors: A
authors: Amin
authors: Hematology Department, Necker Hospital, 149 rue de Sèvres, Paris 75015, France; Centre de référence des mastocytoses (CEREMAST), Necker Hospital, 149 rue de Sèvres, Paris 75015, France.
authors: Marie-Olivia
authors: MO
authors: Chandesris
authors: Clinical Pharmacy, Necker Hospital, 149 rue de Sèvres, Paris 75015, France.
authors: Fabrice
authors: F
authors: Vidal
authors: Clinical Pharmacy, Necker Hospital, 149 rue de Sèvres, Paris 75015, France.
authors: Christophe
authors: C
authors: Merlette
authors: Centre de référence des mastocytoses (CEREMAST), Necker Hospital, 149 rue de Sèvres, Paris 75015, France.
authors: Isabelle
authors: I
authors: Hirsch
authors: Centre de référence des mastocytoses (CEREMAST), Necker Hospital, 149 rue de Sèvres, Paris 75015, France.
authors: Laure
authors: L
authors: Cabaret
authors: Hematology Department, Necker Hospital, 149 rue de Sèvres, Paris 75015, France.
authors: Ana
authors: A
authors: Carvalhosa
authors: Clinical Investigation Department (CIC), Necker Hospital, 149 rue de Sèvres, Paris 75015, France.
authors: Agnès
authors: A
authors: Mogenet
authors: Hematology Department, Necker Hospital, 149 rue de Sèvres, Paris 75015, France.
authors: Laurent
authors: L
authors: Frenzel
authors: Centre de référence des mastocytoses (CEREMAST), Necker Hospital, 149 rue de Sèvres, Paris 75015, France; Hematology Department, Amiens University Hospital, Place Victor Pauchet, Amiens 80054, France.
authors: Gandhi
authors: G
authors: Damaj
authors: Centre de référence des mastocytoses (CEREMAST), Necker Hospital, 149 rue de Sèvres, Paris 75015, France; Infectious Diseases Department (SMIT), Necker Hospital, 149 rue de Sèvres, Paris 75015, France.
authors: Olivier
authors: O
authors: Lortholary
authors: Hematology Department, Necker Hospital, 149 rue de Sèvres, Paris 75015, France; Centre de référence des mastocytoses (CEREMAST), Necker Hospital, 149 rue de Sèvres, Paris 75015, France; CNRS UMR 8147, University Paris V, 15 rue de l'école de médecine, Paris 75006, France.
authors: Olivier
authors: O
authors: Hermine
mesh_terms: D002853:Chromatography, Liquid / Q000379:methods*; D016903:Drug Monitoring / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D016014:Linear Models; D034721:Mastocytosis, Systemic / Q000188:drug therapy*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D019311:Staurosporine; C059539:midostaurin
keywords: AHNMD; ANSM; ASM; Advanced systemic mastocytosis; Agence Nationale de Sécurité du Médicament et des produits de santé; CEREMAST; Centre de Référence des Mastocytoses; DMSO; HESI; Human plasma; IS; Internal Standard; LC–MS/MS; LLQ; MCL; Midostaurin; QC; RSD; Relative Standard Deviation; SM; SRM; TDM; TKI; TUA; Therapeutic drug monitoring; VEGFR; aggressive systemic mastocytosis; associated clonal hematological non-mast cell lineage disease; dimethylsulfoxide; heated electrospray ionization; lower limit of quantiﬁcation; mast cell leukemia; quality control; selected reaction monitoring; systemic mastocytosis; temporary use authorization; therapeutic drug monitoring; tyrosine kinase inhibitor; vascular endothelial growth factor receptor