An Optimized LC-MS/MS Method for Quantification of Sunitinib and N-Desethyl Sunitinib in Human Plasma and Its Application for Therapeutic Drug Monitoring

Abstract

Background: 

Sunitinib (SUN) malate is an oral, multitargeted, tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma, imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. SUN has a narrow therapeutic window and high variability in interpatient pharmacokinetic parameters. Clinical detection methods for SUN and N-desethyl SUN limit the application of SUN to therapeutic drug monitoring. All published methods for quantifying SUN in human plasma require strict light protection to avoid light-induced isomerism or the use of additional quantitative software. To avoid these difficult processes in clinical routines, the authors propose a novel method that merges the peaks of the E-isomer and Z-isomer of SUN or N-desethyl SUN into a single peak.

Methods: 

The E-isomer and Z-isomer peaks of SUN or N-desethyl SUN were merged into a single peak by optimizing the mobile phases to decrease the resolution of the isomers. A suitable chromatographic column was selected to obtain a good peak shape. Thereafter, the conventional and single-peak methods (SPM) were simultaneously validated and compared according to the guidelines published by the Food and Drug Administration in 2018 and the Chinese Pharmacopoeia in 2020.

Results: 

The verification results showed that the SPM was superior to the conventional method in the matrix effect and met the requirements for biological sample analysis. SPM was then applied to detect the total steady-state concentration of SUN and N-desethyl SUN in tumor patients who received SUN malate.

Conclusions: 

The established SPM makes the detection of SUN and N-desethyl SUN easier and faster without light protection or extra quantitative software, making it more appropriate for routine clinical use. The clinical application results showed that 12 patients took 37.5 mg per day, with a median total trough steady-state concentration of 75.0 ng/mL.