Abstract
A sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was established for the quantification of total and unbound concentrations of LY3214996, an extracellular signal-regulated kinase inhibitor; abemaciclib, a cyclin-dependent kinase 4/6 inhibitor; and abemaciclib active metabolites, M2 and M20, in human plasma, brain tumor, and cerebrospinal fluid samples. The method was validated over a concentration range of 0.2-500 nM within a total run time of 3.8 min using isocratic elution on a Kinetex™ Fcolumn. Detection was performed on a Sciex QTRAP 6500+ mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization. The intra- and inter-batch accuracy as well as the precision of the method for all matrices was within ±20% and ≤20% at the lower limit of quantification, and within ±15% and ≤15% for other quality control levels for all analytes. The unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium dialysis. The validated method was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib.
Overview
- The study aims to develop a sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantification of total and unbound concentrations of LY3214996, an extracellular signal-regulated kinase inhibitor; abemaciclib, a cyclin-dependent kinase 4/6 inhibitor; and abemaciclib active metabolites, M2 and M20, in human plasma, brain tumor, and cerebrospinal fluid samples. The method was validated over a concentration range of 0.2-500 nM within a total run time of 3.8 min using isocratic elution on a Kinetex™ Fcolumn. Detection was performed on a Sciex QTRAP 6500+ mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization. The intra- and inter-batch accuracy as well as the precision of the method for all matrices was within ±20% and ≤20% at the lower limit of quantification, and within ±15% and ≤15% for other quality control levels for all analytes. The unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium dialysis. The validated method was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib.
Comparative Analysis & Findings
- The study did not provide a direct comparative analysis of the outcomes observed under different experimental conditions or interventions. However, the method developed in the study was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib. The results of the study showed that the developed method was sensitive, accurate, and precise for the quantification of total and unbound concentrations of LY3214996, abemaciclib, and their active metabolites in various matrices. The unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium dialysis. The study highlights the importance of developing sensitive and accurate methods for the quantification of drug concentrations in various matrices, which can aid in the monitoring of drug efficacy and toxicity in clinical trials and clinical practice.
Implications and Future Directions
- The study's findings have significant implications for the development of sensitive and accurate methods for the quantification of drug concentrations in various matrices, which can aid in the monitoring of drug efficacy and toxicity in clinical trials and clinical practice. The developed method can be further optimized and validated for the quantification of other drugs and their metabolites in various matrices. Future research directions could include the development of methods for the quantification of drug concentrations in other biological fluids, such as urine and bile, and the integration of the developed method with other analytical techniques, such as gas chromatography, to provide a comprehensive analysis of drug concentrations in various matrices. Additionally, the developed method can be applied in the development of personalized medicine strategies by providing information on drug pharmacokinetics and pharmacodynamics in individual patients.