Simultaneous determination of LY3214996, abemaciclib, and M2 and M20 metabolites in human plasma, cerebrospinal fluid, and brain tumor by LC-MS/MS

Tigran Margaryan; Mackenna Elliott; Nader Sanai; Artak Tovmasyan

doi:10.1016/j.jpha.2022.05.003

Volume 12 Issue 4

Sep. 2022

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Tigran Margaryan, Mackenna Elliott, Nader Sanai, Artak Tovmasyan. Simultaneous determination of LY3214996, abemaciclib, and M2 and M20 metabolites in human plasma, cerebrospinal fluid, and brain tumor by LC-MS/MS[J]. Journal of Pharmaceutical Analysis, 2022, 12(4): 601-609. doi: 10.1016/j.jpha.2022.05.003

Citation:

Tigran Margaryan, Mackenna Elliott, Nader Sanai, Artak Tovmasyan. Simultaneous determination of LY3214996, abemaciclib, and M2 and M20 metabolites in human plasma, cerebrospinal fluid, and brain tumor by LC-MS/MS[J]. Journal of Pharmaceutical Analysis, 2022, 12(4): 601-609. doi: 10.1016/j.jpha.2022.05.003

Citation:

Tigran Margaryan, Mackenna Elliott, Nader Sanai, Artak Tovmasyan. Simultaneous determination of LY3214996, abemaciclib, and M2 and M20 metabolites in human plasma, cerebrospinal fluid, and brain tumor by LC-MS/MS[J]. Journal of Pharmaceutical Analysis, 2022, 12(4): 601-609. doi: 10.1016/j.jpha.2022.05.003

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Simultaneous determination of LY3214996, abemaciclib, and M2 and M20 metabolites in human plasma, cerebrospinal fluid, and brain tumor by LC-MS/MS

doi: 10.1016/j.jpha.2022.05.003

Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ, 85013, USA

Funds:

The authors are thankful for funding provided by the Ben and Catherine Ivy Foundation.

Received Date: Jan. 22, 2022
Accepted Date: May 14, 2022
Rev Recd Date: May 13, 2022
Publish Date: May 20, 2022

Abstract

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^TM F₅ column. 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.
- LC-MS/MS,
- LY3214996,
- Abemaciclib,
- Brain tumor penetration,
- Equilibrium dialysis

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