Meeting Report: Metabolites in Safety Testing (MIST) Symposium—Safety Assessment of Human Metabolites: What’s REALLY Necessary to Ascertain Exposure Coverage in Safety Tests?

In the 2012 AAPS metabolites in safety testing (MIST) symposium held in Chicago, IL, USA, on October 15, 2012, regulatory experts and industrial scientists joined together to discuss their perspectives and strategies in addressing contemporary MIST recommendations (FDA 2008, International Conference on Harmonization (ICH) M3(R2), ICH M(R2) Q&A). Overall, these regulatory guidances indicate that metabolites identified in human plasma should circulate at similar or greater concentrations in at least one of the animal species used in nonclinical safety assessment of the parent drug. However, synthetic standards for the metabolites often do not exist or they are intractable to synthesize, thus introducing multiple challenges in drug development for the quantitative comparison of metabolites between human and animals. A tiered bioanalytical strategy for metabolite analysis is a prevalent approach to demonstrate coverage in animals. Recent developments in bioanalytical methodology have yielded several time- and resource-sparing strategies to provide fit-for-purpose approaches that can enable critical decisions related to metabolite quantification and monitoring in plasma. This report summarizes the presentations and panel discussions at the symposium.

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[2]  Nirmala Raghavan,et al.  LC-MS/MS-based approach for obtaining exposure estimates of metabolites in early clinical trials using radioactive metabolites as reference standards. , 2007, Drug metabolism letters.

[3]  Shibing Deng,et al.  A Simple Liquid Chromatography-Tandem Mass Spectrometry Method to Determine Relative Plasma Exposures of Drug Metabolites across Species for Metabolite Safety Assessments , 2010, Drug Metabolism and Disposition.

[4]  P. Timmerman,et al.  Best practices in a tiered approach to metabolite quantification: views and recommendations of the European Bioanalysis Forum. , 2010, Bioanalysis.

[5]  Saralees Nadarajah,et al.  Letter to the editor , 2007, Int. Trans. Oper. Res..

[6]  Adedayo Adedoyin,et al.  Obtaining exposures of metabolites in preclinical species through plasma pooling and quantitative NMR: addressing metabolites in safety testing (MIST) guidance without using radiolabeled compounds and chemically synthesized metabolite standards. , 2009, Chemical research in toxicology.

[7]  G. S. Walker,et al.  Validation of Isolated Metabolites from Drug Metabolism Studies as Analytical Standards by Quantitative NMR , 2011, Drug Metabolism and Disposition.

[8]  Chungping Yu,et al.  A rapid method for quantitatively estimating metabolites in human plasma in the absence of synthetic standards using a combination of liquid chromatography/mass spectrometry and radiometric detection. , 2007, Rapid communications in mass spectrometry : RCM.

[9]  Jianyao Wang,et al.  Nuclear magnetic resonance spectroscopy as a quantitative tool to determine the concentrations of biologically produced metabolites: implications in metabolites in safety testing. , 2009, Chemical research in toxicology.

[10]  Abigail Jacobs,et al.  Drug metabolites in safety testing. , 2003, Toxicology and applied pharmacology.

[11]  S. Chowdhury,et al.  Determination of exposure multiples of human metabolites for MIST assessment in preclinical safety species without using reference standards or radiolabeled compounds. , 2010, Chemical research in toxicology.

[12]  P. Yi,et al.  A radiocalibration method with pseudo internal standard to estimate circulating metabolite concentrations. , 2010, Bioanalysis.

[13]  R Scott Obach,et al.  Metabolites and safety: What are the concerns, and how should we address them? , 2006, Chemical research in toxicology.

[14]  R. Obach,et al.  A Simple Liquid Chromatography-Tandem Mass Spectrometry Method to Determine Relative Plasma Exposures of Drug Metabolites across Species for Metabolite Safety Assessments (Metabolites in Safety Testing). II. Application to Unstable Metabolites , 2012, Drug Metabolism and Disposition.