Abstract
Cross validation studies for bioanalytical methods are important to ensure that assay data from all study sites where sample analysis is performed can be compared throughout clinical trials. To support global clinical studies of lenvatinib, a novel multi-targeted tyrosine kinase inhibitor, seven bioanalytical methods by liquid chromatography with tandem mass spectrometry (LC-MS/MS) were developed at five laboratories. In this study, methods were initially validated at each laboratory according to bioanalytical guidelines. For subsequent inter-laboratory cross validation, quality control (QC) samples and clinical study samples with blinded lenvatinib concentrations were assayed to confirm comparable assay data. Lenvatinib and an internal standard were extracted by protein precipitation, liquid-liquid extraction, or solid phase extraction and then detected in positive ion electrospray mode by multiple reaction monitoring using LC-MS/MS. The assay method developed at each laboratory was successfully validated with parameters within the acceptance criteria recommended by the guidelines. In the cross validation study, accuracy of QC samples was within± 15.3% and percentage bias for clinical study samples was within± 11.6%. These findings suggest that lenvatinib concentrations in human plasma can be compared across laboratories and clinical studies.
Highlights
Lenvatinib is a novel multi-targeted tyrosine kinase inhibitor which inhibits vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor α, c-Kit, and RET [1,2,3]
To the best of our knowledge, two bioanalytical methods for lenvatinib have been reported; lenvatinib and its metabolites assay in human plasma, urine and faeces [4] and lenvatinib assay in human serum and phosphate buffered saline for protein binding studies [5]
The first objective of this study is to show a comprehensive list of assay methods for lenvatinib and its validation parameters at each laboratory
Summary
Lenvatinib is a novel multi-targeted tyrosine kinase inhibitor which inhibits vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor α, c-Kit, and RET (rearranged during transfection) [1,2,3]. A number of clinical studies were conducted across the globe and five bioanalytical laboratories established assay methods for the determination of lenvatinib concentrations in human plasma. Bioanalytical methods for the determination of lenvatinib concentrations in human plasma are reported. The first objective of this study is to show a comprehensive list of assay methods for lenvatinib and its validation parameters at each laboratory. The second objective of this study is to assess whether all the bioanalytical laboratories of lenvatinib assay demonstrate comparable data to ensure that pharmacokinetic parameters of lenvatinib can be compared across clinical trials. Successful validation of each method is a pre-requisite to performing clinical sample assay, cross validation studies are required to compare concentrations among bioanalytical methods and/or laboratories as per the bioanalytical guidelines by European Medicines Agency
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