Quantification of sunitinib and N-desethyl sunitinib in human EDTA plasma by liquid chromatography coupled with electrospray ionization tandem mass spectrometry: validation and application in routine therapeutic drug monitoring.

For determination of sunitinib and N-desethyl sunitinib in human EDTA plasma samples, high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used. Validation experiments according to Food and Drug Administration guidelines were performed. In addition, the results of 25 analytical runs with 58 patient samples using 8 calibrators and 3 levels of quality control (QC) samples per analysis were compared with the results of analyses using only 3 calibrators and 1 QC sample to accelerate sample turnaround time. The method comparison experiment was performed according to international guidelines.

This method has been applied successfully for routine TDM purposes for patients treated with sunitinib. Moreover, reliable results with a rapid turnaround time were obtained when performing a short analytical run containing only 3 calibrators and 1 QC sample.

The HPLC-MS/MS method was validated over a linear range from 2.5 to 500 ng/mL using 50 μL plasma volumes, with good intra- and interassay accuracy and precision. In addition, the mean of the absolute differences between the compared methods was only -0.66 ng/mL (mean of relative differences, -0.85%), which is not a clinically relevant difference.

Given the low therapeutic index, the large interindividual variability in systemic exposure and the positive exposure-efficacy relationship of sunitinib, there is a rationale for therapeutic drug monitoring (TDM) of sunitinib. To support TDM, a method for determination of sunitinib and its active metabolite (N-desethyl sunitinib) has been developed and validated.