Volumetric absorptive microsampling for lumateperone analysis: method validation and stability evaluation

Lumateperone is a recently approved atypical antipsychotic for the treatment of schizophrenia, with moderate adverse effects. However, the risk of toxicity, mainly due to possible multidrug coadministration, makes the therapeutic drug monitoring (TDM) approach crucial for developing personalised therapies and reducing side effects. In the TDM research field, microsampling represents an innovative and effective approach based on the collection and analysis of small sample volumes (< 100 μL), exhibiting many advantages (such as enhanced analyte stability, minimally invasive procedures and simplified sample storage and transport) and improving patient adherence. For the first time, an analytical methodology based on microsampling was developed and fully validated for the analysis of lumateperone in capillary blood microsamples, by means of volumetric absorptive microsampling (VAMS) in comparison with plasma analysis, with the future perspective of supporting the TDM of psychiatric patients. A reliable and streamlined VAMS protocol was optimised, and an original HPLC-MS/MS method was developed and validated, granting satisfactory results on simulated samples in terms of linearity, precision, extraction yield and matrix effect. Method reliability was successfully tested by comparing the VAMS performance with standard in-tube fluid plasma, and short- and medium-term comparative stability assays confirmed the enhancement of analyte stability obtained in dried microsamples with respect to plasma samples. This is the first analytical method based on microsampling able to provide reliable data when compared to plasma analysis and promising for future TDM applications in patients treated with lumateperone, thus offering significant advantages over conventional blood/plasma sampling in terms of collection, storage and processing.