A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the "Metabolites in Safety Testing" Regulatory Guidance

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Simone SchadtR Scott Obach

Abstract

Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated, which has led to more frequent determination of human metabolite profiles from multiple ascending-dose clinical studies. Generating a comprehensive and quantitative profile of huma...Continue Reading

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Citations

Apr 3, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ryan H TakahashiShuguang Ma
Jun 18, 2019·Current Drug Metabolism·Selvan RavindranVedika Desai
May 12, 2019·Toxics·Michael A MalfattiKenneth W Turteltaub
Nov 22, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Simone SchadtChristoph Funk
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Jun 26, 2020·Acta Pharmacologica Sinica·Qian-Qian TianDa-Fang Zhong
May 10, 2020·Clinical Pharmacology and Therapeutics·Bianca D van GroenSaskia N de Wildt
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Jul 22, 2021·APL Bioengineering·Chase P MoncktonSalman R Khetani
Aug 1, 2021·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Daigo AsanoKouichi Yoshinari
Nov 21, 2020·ACS Medicinal Chemistry Letters·Julia Shanu-WilsonJason Boer
Feb 26, 2020·Journal of Medicinal Chemistry·Matthew A CernyGregory S Walker
Dec 21, 2019·Chemical Research in Toxicology·Andreas ZellerSimone Schadt
Nov 15, 2021·Drug Discovery Today·Kit-Kay MakMallikarjuna Rao Pichika
Sep 11, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Zeyuan WangKen Korzekwa

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