title: Validation of an HPLC-UV method for sorafenib determination in human plasma and application to cancer patients in routine clinical practice.
abstract: Sorafenib, a new oral multikinase inhibitor with antiangiogenic properties, has demonstrated preclinical and clinical activity against several tumor types. The aims of this study were to validate a method for the measurement of sorafenib in plasma from cancer patients, then to test this method in clinical practice. Following liquid-liquid extraction, the compounds were separated with gradient elution (on a C18 ultrasphere ODS column using a mobile phase of acetonitrile/20 mM ammonium acetate), then detected at 255 nm. The calibration was linear in the range 0.5-20 mg/L. Intra- and inter-assay precision was lower than 7 and 10%, respectively, at 0.5, 3 and 20 mg/L. Plasma sorafenib concentrations were measured in 22 cancer patients (99 samples). The mean trough sorafenib concentration (C(min)) and concentration at peak were 4.3+/-2.5 mg/L (n=68, CV=57.5%) and 6.2+/-3.0 mg/L (n=31, CV=47.5%), respectively. Mean sorafenib C(min) in eight patients who experienced grade 3 drug-related adverse events was approximately 1.5-fold greater than that observed in the remaining patients (7.7+/-3.6 mg/L vs. 4.4+/-2.4 mg/L, P=0.0083). In conclusion, the method was successfully used in routine practice to monitor plasma concentrations of sorafenib in cancer patients. Finally, large interindividual variability and higher exposure in patients experiencing severe toxicity support the need for therapeutic drug monitoring to ensure an optimal exposure to sorafenib.
authors.affiliation: Laboratoire de Pharmacologie-Toxicologie, Service de Pharmacie, France. benoit.blanchet@cch.aphp.fr
authors.forename: B
authors.initials: B
authors.lastname: Blanchet
authors.forename: B
authors.initials: B
authors.lastname: Billemont
authors.forename: J
authors.initials: J
authors.lastname: Cramard
authors.forename: A S
authors.initials: AS
authors.lastname: Benichou
authors.forename: S
authors.initials: S
authors.lastname: Chhun
authors.forename: L
authors.initials: L
authors.lastname: Harcouet
authors.forename: S
authors.initials: S
authors.lastname: Ropert
authors.forename: A
authors.initials: A
authors.lastname: Dauphin
authors.forename: F
authors.initials: F
authors.lastname: Goldwasser
authors.forename: M
authors.initials: M
authors.lastname: Tod
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D011786:Quality Control; D012015:Reference Standards; D015203:Reproducibility of Results; D000077157:Sorafenib; D013048:Specimen Handling; D013056:Spectrophotometry, Ultraviolet
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib