Determination of Blood Concentration of Lenvatinib in Human Plasma by LC-MS/MS and Clinical Application Analysis

OBJECTIVE To establish an LC-MS/MS method for determining the concentration of lenvatinib in plasma and apply it to clinical drug monitoring.

METHODS The determination was performed using Waters HSS T3 chromatographic column with lenvatinib-d5 isotope as the internal standard, gradient elution was performed with deionized water(containing 0.1% formic acid) and acetonitrile(containing 0.1% formic acid) as the mobile phases at a flow rate of 0.4 mL·min⁻¹, column temperature of 40 ℃, and injection volume of 2 μL. Multiple reaction monitoring with electrospray positive ion(ESI⁺) mode was used for detection. The patients with hepatocellular carcinoma receiving treatment with lenvatinib in general surgery department of The First Affiliated Hospital of Nanchang University were selected and the blood concentration of lenvatinib were measured.

RESULTS The constructed detection method for lenvatinib had a good linear relationship within the range of 1.15–410.38 ng·mL⁻¹(r>0.999), with a lower limit of quantification of 1.15 ng·mL⁻¹, which could meet clinical applications. The intra day and inter day accuracy ranged from 96.97% to 102.68%, and the RSD of precision was less than 15%. The extraction recovery rate ranged from 94.21% to 100.48%, and the normalized matrix effect of the internal standard ranged from 99.75% to 108.84%, with RSD less than 15%. The accuracy of stability testing ranged from 97.11% to 103.78%, with RSD less than 15%. The methodological validation met the requirements for biological sample analysis. The 54 individuals were tested for the concentration of lenvatinib, with concentrations ranging from 2.387 to 67.453 ng·mL⁻¹ and an average concentration of 21.60 ng·mL⁻¹, showing significant individual differences.

CONCLUSION The LC-MS/MS method constructed for determining the concentration of lenvatinib is accurate and efficient, and can be used for monitoring the use of lenvatinib and pharmacokinetic studies.