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.
Article: Preparation, in vitro release, and pharmacokinetics in rabbits of lyophilized injection of sorafenib solid lipid nanoparticles.[show abstract] [hide abstract]
ABSTRACT: Sorafenib solid lipid nanoparticles (S-SLN) were prepared by emulsion evaporation-solidification at low temperature. Morphology was examined by transmission electron microscope. Particle size and zeta potential were determined by laser granularity equipment. Encapsulation efficiency (EE) was detected by Sephadex gel chromatography and high-performance liquid chromatography (HPLC). The in vitro release profile of S-SLN was studied with dialysis technology. The lyophilized injection of S-SLN was prepared by freeze drying and analyzed by differential scanning calorimetry. The plasma concentration of sorafenib in blood was determined by HPLC. The solid lipid nanoparticles assumed a spherical shape with an even distribution of diameter and particle size 108.23 ± 7.01 nm (n = 3). The polydispersity index, zeta potential, and EE were determined to be 0.25 ± 0.02, -16.37 ± 0.65 mV, and 93.49% ± 1.87%, respectively (n = 3). The in vitro release accorded with the Weibull distribution model. An equal volume of 15% (w/v) mannitol performed better as the protective agent for a lyophilized injection of S-SLN with a new material phase formation. The pharmacokinetic processes of sorafenib solution and lyophilized injection of S-SLN in vivo were in accordance with the two-compartment and one-compartment models, respectively. S-SLN nanoparticles are thus considered a promising drug-delivery system.International Journal of Nanomedicine 01/2012; 7:2901-10. · 3.13 Impact Factor
Article: Sarcopenia predicts early dose-limiting toxicities and pharmacokinetics of sorafenib in patients with hepatocellular carcinoma.[show abstract] [hide abstract]
ABSTRACT: Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment.PLoS ONE 01/2012; 7(5):e37563. · 4.09 Impact Factor