A simple and rapid UHPLC-MS/MS method for the quantitation of the dual aurora kinase A/B inhibitor SCH-1473759 in murine plasma
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Marco A Ferraz Nogueira Filho1, Cody J Peer2, Jeffers Nguyen2
1Clinical Pharmacology Program, Office of the Clinical Director, National Cancer Institute, Bethesda, MD, USA; CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, Brazil.
Abstract:
The Aurora kinase family facilitates cell division through various processes and is overexpressed in a wide variety of human cancers, leading to aneuploidy. For that reason, these enzymes are currently targets of a rising class of anticancer drugs, with some molecules already in therapeutic use. In this study, a new UHPLC-MS/MS method was developed and validated to quantitate a new pan Aurora kinase inhibitor still in preclinical development, SCH-1473759. This bioanalytical method employed a liquid-liquid extraction from plasma using ethyl acetate before evaporation. Calibration range encompassed 0.5-2500ng/mL. The inter- and intra-day accuracy and precision were assessed over five quality control levels; all within limits required by the FDA guidelines. Assay applicability was demonstrated in a first-in-animals study with oral administration, where the maximum plasma concentration (34ng/mL) occurred at 1h, the half-life (1h) was consistent with a previous IV study, and oral bioavailability was poor (F=0.002).
Insights
A new bioanalytical method quantifies the pan Aurora kinase inhibitor SCH-1473759 in preclinical studies. The assay demonstrated poor oral bioavailability in animals, indicating challenges for this anticancer drug candidate.
Area of Science:
- Pharmacology and Toxicology
- Analytical Chemistry
- Oncology
Background:
- Aurora kinases are crucial for cell division and are frequently overexpressed in human cancers, driving aneuploidy.
- These kinases are validated targets for novel anticancer therapies, with several drugs in clinical use or development.
- SCH-1473759 is a novel pan Aurora kinase inhibitor undergoing preclinical investigation.
Purpose of the Study:
- To develop and validate a sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for quantifying SCH-1473759 in plasma.
- To assess the pharmacokinetic profile of SCH-1473759 following oral administration in an animal model.
Main Methods:
- Plasma samples were prepared using liquid-liquid extraction with ethyl acetate.
- Quantification was performed using UHPLC-MS/MS over a calibration range of 0.5–2500 ng/mL.
- Method validation included assessment of accuracy and precision at five quality control levels, adhering to FDA guidelines.
Main Results:
- The validated UHPLC-MS/MS method demonstrated excellent accuracy and precision.
- In preclinical studies, oral administration of SCH-1473759 resulted in a maximum plasma concentration of 34 ng/mL at 1 hour.
- The drug exhibited a short half-life of 1 hour and very poor oral bioavailability (F=0.002).
Conclusions:
- A robust bioanalytical method for SCH-1473759 has been successfully developed and validated.
- The preclinical pharmacokinetic data reveal significant challenges with the oral delivery and bioavailability of SCH-1473759, potentially limiting its therapeutic utility.
- Further development may require alternative formulations or administration routes to improve drug exposure.
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