Bioanalysis of Alectinib and Metabolite M4 in Human Plasma, Cross-Validation and Impact on PK Assessment

Abstract

Background: Alectinib is a novel anaplastic lymphoma kinase (ALK) inhibitor for treatment of patients with ALK-positive non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. To support clinical development, concentrations of alectinib and metabolite M4 were determined in plasma from patients and healthy subjects. Methods: LC–MS/MS methods were developed and validated in two different laboratories: Chugai used separate assays for alectinib and M4 in a pivotal Phase I/II study while Roche established a simultaneous assay for both analytes for another pivotal study and all other studies. Conclusion: Cross-validation assessment revealed a bias between the two bioanalytical laboratories, which was confirmed with the clinical PK data between both pivotal studies using the different bioanalytical methods.

Keywords::

• alectinib
• Alecensa^®
• anaplastic lymphoma kinase
• column switching
• cross-validation
• LC–MS/MS
• matrix effect
• non-small-cell lung cancer
• phospholipids
• plasma

Supplementary Data

Financial & competing interests disclosure

K Heinig, E Guerini, D Fraier, P Morcos, L Yu and S Bansal are employed by F. Hoffmann-La Roche Ltd. K Miya and T Kamei are employed by Chugai Pharmaceuticals Co. Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

The authors are thankful to Y Kimura and M Nakamura for their skillful analytical performances at Chugai lab. We thank Q² Solutions, a Quintiles Quest Joint Venture, for supporting the method validation, cross-validation and samples analysis.