Abstract
Lenvatinib (LENVA) is an oral antineoplastic drug used for the treatment of hepatocellular carcinoma and thyroid carcinoma. LENVA therapeutic drug monitoring (TDM) should be mandatory for a precision medicine to optimize the drug dosage. To this end, the development of a sensitive and robust quantification method to be applied in the clinical setting is essential. The aim of this work was to develop and validate a sensitive, rapid, and cost-effective LC-MS/MS method for the quantification of LENVA in human plasma. On this premise, sample preparation was based on a protein precipitation and the chromatographic separation was achieved on a Synergi Fusion RP C18 column in 4 min. The method was completely and successfully validated according to European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines, with good linearity in the range of 0.50–2000 ng/mL (R≥0.9968). Coefficient of variation (CV) for intra- and inter-day precision was ≤11.3% and accuracy ranged from 96.3 to 109.0%, internal standard normalized matrix effect CV% was ≤2.8% and recovery was ≥95.6%. Successful results were obtained for sensitivity (signal to noise (S/N) ratio >21) and selectivity, dilution integrity (CV% ≤ 4.0% and accuracy 99.9–102%), and analyte stability under various handling and storage conditions both in matrix and solvents. This method was applied to quantify LENVA in patient’s plasma samples and covered the concentration range achievable in patients. In conclusion, a sensitive and robust quantification method was developed and validated to be applied in the clinical setting.
Highlights
LC-MS/MS analytical methods for therapeutic drug monitoring (TDM) application should meet the demands for low sample volumes, simplicity of sample preparation, short run times, reliability, robustness, selectivity, precision, sensitivity, and cost-effectiveness
We developed a new LC-MS/MS method for LENVA quantification in human plasma which required just 100 μL of patient’s plasma
The proposed method was characterized by a wide analytical range (0.50–2000 ng/mL) which properly covered the therapeutic plasma concentrations of hepatocellular carcinoma (HCC) patients, and makes it applicable for PK investigations in patients affected by other pathologies which require the use of LENVA at higher doses (24 mg/day), in which the mean value of Cmax at steady state ranged from 430–660 ng/mL [19] or even for hypothetical future applications whether higher doses of LENVA may be investigated
Summary
A new LC-MS/MS method for lenvatinib plasma quantification boards or activities as a speaker from Amgen, Astrazeneca, Daichii-Sankyo, Eisai, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Seagen, Takeda. He received research funding form Astrazeneca, Eisai and Roche, and travel grants from Celgene, GlaxoSmithKline and Roche. It was approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) as monotherapy for the treatment of differentiated thyroid carcinoma (DTC), and hepatocellular carcinoma (HCC) [2, 3]. FDA approved LENVA for the treatment of advanced renal cell carcinoma [2]
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