QPS Offers Cost Effective Mass Spectrometric Solutions to Address MIST Issues

To improve patient safety and to avoid costly late stage failures, the pharmaceutical industry is pushing for an in-depth understanding of the qualitative and quantitative differences in drug metabolism between animals used in nonclinical safety assessments and humans as early as possible during drug development (1-2). This requirement is clearly defined in the ICH M3 and the US FDA Safety Testing of Drug Metabolites guidelines. While definitive data can be obtained through the use of radiolabeled drugs, data from human radiolabeled AME studies are typically not available until Phase II, and single dose radiolabel studies do not provide information about metabolites present at steady-state drug concentrations. Therefore, we are seeing an increased use of samples from multiple ascending dose (MAD) clinical studies and 28-day toxicity studies to fill the data gap and to gain an early understanding about steady-state circulating drug metabolites in humans using technologies that have become available. In these instances, selected tox samples and MAD samples are analyzed by ultra-high pressure liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) techniques and associated post-data collection software solutions such as mass-defect filtering (MDF), isotope pattern filtering (IPF), and high resolution background subtraction to generate metabolite data at steady-state. The data generated from the systematic investigation of non-radiolabeled human and preclinical species samples using HRMS-based metabolite detection, characterization, and semi-quantification methodology are adequate to address MIST needs during the drug discovery and development process.

  • S. Ma, Z. Li, K. J. Lee, and S. K. Chowdhury (2011). "Determination of exposure multiples of human metabolites for MIST assessment in preclinical safety species without using reference standards or radiolabeled compounds." Chem Res Toxicol 23(12): 1871-3.
  • R. Ramanathan, J. L. Josephs, M. Jemal, M. Arnold, and W. G. Humphreys (2010). "Novel MS solutions inspired by MIST." Bioanalysis 2(7): 1291-1313.

QPS, LLC Zamas Lam, PhD; VP Non-Clinical Development;

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