Abstract
Enabled by liquid chromatography/tandem mass spectrometry (LC/MS/MS) based multiple-component assays, cassette dosing is an effective tool to significantly improve the throughput for pharmacokinetic (PK) screening. However, this higher throughput approach also carries its limitations. In addition to potential drug–drug interactions, the multiple-component assays used to analyze cassette-dosing samples are also subject to potentially serious errors. In this work, a systematic approach has been taken to investigate each critical step in the development of a specific, accurate, and rapid multiple-component assay. These steps include pool selection, sample preparation, chromatographic separation and assay qualification. Based on the results, effective strategies for the development of multiple-component assays are proposed which involve proactive pool assignment, on-line extraction, monolithic-column separation and cassette/discrete response comparison. The effectiveness of these strategies was evaluated by comparing the pharmacokinetic results between discrete and cassette studies for over 20 compounds. Statistically good correlation between discrete and cassette data was established.
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