Volumetric absorptive microsampling as a suitable tool to monitor tyrosine kinase inhibitors

Abstract

Therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKIs) shows significant potential in guiding personalized anticancer treatment. Dried blood microsampling could be a valuable alternative for traditional plasma sampling to provide TDM results faster and to reach a wider audience. Sample collection is easy and patient friendly as only a small volume of blood is collected via a fingerprick. This enables the possibility of home sampling by the patients themselves. Therefore, an LC-MS/MS method was developed and validated for the quantification of bosutinib, dasatinib, gilteritinib, ibrutinib, imatinib, midostaurin, nilotinib and ponatinib in dried blood samples collected via volumetric absorptive microsampling (VAMS). A VAMS device collects a fixed volume of blood (± 10 µL), irrespective of the sample's hematocrit (Hct). During method validation, special attention was paid to the possible impact of Hct (range 0.18-0.55) on matrix effect (ME), robustness of the extraction, and accuracy of the method. The method was successfully validated based on international guidelines in terms of calibration curves, precision (within-run CV 2.20-14.8%; between-run CV 2.40-12.3%), accuracy (within-run bias 0.34-12.5%; between-run bias -0.15 to 16.2%), carry-over and selectivity. IS-compensated ME and recovery were Hct independent and no significant impact of Hct on the accuracy of the TKI quantifications was observed. All TKIs were stable in VAMS samples stored at -20 °C, 4 °C and room temperature for at least 4 weeks and for 2 days at 60 °C (except ibrutinib). Lastly, we demonstrated a good agreement between liquid blood obtained from patients on TKI treatment and VAMS samples prepared from that venous blood. As this implies that there is no methodological impact of liquid versus dried blood analysis, the presented method can be applied in clinical follow-up studies for determining TKIs in (capillary) VAMS samples with varying Hct levels.

Keywords: Dried blood microsampling; LC-MS/MS; Therapeutic drug monitoring; Tyrosine kinase inhibitors; Volumetric absorptive microsampling.