title: A method to measure deferasirox in plasma using HPLC coupled with MS/MS detection and its potential application.
abstract: Iron overload resulting from transfusion dependency in some patients with chronic anaemia can be prevented by chelation. Deferasirox is an oral alternative to the well studied but inconvenient deferroxamine therapy. The pharmacokinetic parameters of this new drug suggest potential interindividual variability and patients might benefit from pharmacologic drug monitoring. We developed an liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) method to quantify deferasirox in plasma. After protein precipitation, samples were injected onto an XTerra RP18 column with a gradient of acetonitrile and formiate buffer (4 mM, pH 3.0) with 5% methanol. Detection by electrospray ionization mass-spectrometry was performed using the multiple reaction monitoring mode. Sixty-three samples from patients treated with deferasirox were then analyzed to evaluate pharmacokinetic/pharmacodynamic relationships. Calibration curves were linear from 0.5 to 40 microg/mL. Interday and intraday precision were lower than 8.9% and 7.3%, respectively. Bias did not exceed 12.7%. Plasma iron overload did not interfere with analysis. Plasma drug concentrations of patients treated by deferasirox were compared with plasma ferritin, considered as a marker of treatment efficacy. No statistically significant correlation was observed, though higher ferritin concentrations (>1000 microg/L, n = 30) were observed in patients with lower mean deferasirox concentration (9.5 +/- 9.1 microg/mL). This simple method is suitable for routine monitoring of deferasirox concentrations in plasma as it requires very few steps and has a short runtime. It allows evaluation of patient compliance, drug-drug interactions, and further investigations of pharmacokinetic/pharmacodynamic relationships.
authors.affiliation: Département de Pharmacologie Clinique et Toxicologie, CHU de Bordeaux, Bordeaux, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Chauzit
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bouchet
authors.forename: Marguerite
authors.initials: M
authors.lastname: Micheau
authors.forename: François Xavier
authors.initials: FX
authors.lastname: Mahon
authors.forename: Nicholas
authors.initials: N
authors.lastname: Moore
authors.forename: Karine
authors.initials: K
authors.lastname: Titier
authors.forename: Mathieu
authors.initials: M
authors.lastname: Molimard
mesh_terms: D001565:Benzoates / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D001800:Blood Specimen Collection; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D000077588:Deferasirox; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D006801:Humans; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics; D019190:Iron Overload / Q000097:blood / Q000188:drug therapy; D011786:Quality Control; D012015:Reference Standards; D015203:Reproducibility of Results; D012997:Solvents; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D001565:Benzoates; D007502:Iron Chelating Agents; D012997:Solvents; D014230:Triazoles; D000077588:Deferasirox