Development of an LC-MS/MS Method for Simultaneous Quantification of Ibrutinib and Ritonavir in Plasma and Dried Plasma Spots

The instability of ibrutinib in plasma at room temperature necessitates temperature-controlled sample transport, complicating therapeutic drug monitoring (TDM) and multicenter studies. Dried plasma spots (DPSs) offer a potential advantage by enabling sample storage and transport under ambient conditions. The aim of this study was to develop and validate an LC-MS/MS method for the simultaneous quantification of ibrutinib and ritonavir in plasma and DPSs. Following validation of an extended plasma calibration range, DPS method development included card selection and subsequent validation in accordance with ICH M10 and EMA guidelines. The analytical method demonstrated robust performance in plasma for both analytes. For DPS sampling, ritonavir fulfilled all validation criteria. In contrast, ibrutinib showed significant instability in DPS samples at room temperature after 48 h and did not meet the predefined acceptance criteria under these conditions. Refrigerated storage improved stability within the acceptance criteria for at least one week. The developed method is suitable for simultaneous quantification of ibrutinib and ritonavir in plasma and for ritonavir in DPSs. While DPS sampling may offer logistical advantages, its successful application is dependent on analyte stability. For ibrutinib, the requirement for refrigerated storage limits the anticipated benefits, and further research is needed to optimize dried sampling strategies.