Therapeutic drug monitoring of protein kinase inhibitors is a widely practiced worldwide. Based on the example of ripretinib dosage requested by a clinician, we detailed the process of method development, using a literature-based approach while ensuring the sustainability of the method to be as environmentally friendly as possible. Therefore, an UPLC-MS/MS method for ripretinib and its active metabolite was optimized and validated using the corresponding stable isotopic internal standards in human plasma. The procedure has employed mobile phase mixture of water with 1% acetic acid and 0.1% formic acid, and acetonitrile. Positive electrospray ionization was performed coupling with multiple reaction monitoring of m/z 510.4→417.4 and 510.4→389.4 for ripretinib, and 496.3→403.3 and 496.3→375.3 for N-desmethyl-ripretinib. The method was successfully validated according the current version of ICH Guideline provided by the EMA. The greenness assessment score of this procedure was evaluated and compared with previously published approaches using the AGREE metric. The validated UPLC-MS/MS method successfully monitored ripretinib and its metabolite concentrations in clinical and pre-clinical models.

The authors have declared no competing interest.

This study was supported by Bordeaux University Hospital, Bordeaux Institute of Oncology (BRIC) and Association pour la Recherche sur les Tumeurs Cerebrales (N 283008). AS and AB were supported by a fellowship from the Fondation de France.

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Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Institutional review board of Institut Bergonie (Clinical Research College) gave ethical approval for this work

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All data produced in the present study are available upon reasonable request to the authors