Metabolites in Safety Testing (MIST)
Compare the exposure of the major metabolites in steady state plasma in human and in toxicological species when a metabolite (especially Phase I metabolite) in human plasma accounting for more than 10% AUC to evaluate whether the safety of the major metabolites has been adequately assessed or not.
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Overview
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Assays
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Study Strategies
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Case Study
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Regulatory Guidance
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Experience
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Instruments and Software
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FAQs
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Related Resources
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Related Services
Overview
WuXi AppTec DMPK can provide MIST research services and guide analytical decisions in a progressive manner based on experimental results. Our team has over 15 years of industry experience and includes dozens of experienced metabolic researchers. We have established a state-of-the-art platform equipped with various models of high-resolution mass spectrometry, including the Orbitrap Eclipse™ Tribrid™, Orbitrap Exploris™ 480, Q Exactive™ (QE), Q Exactive™ PLUS, Q Exactive™ HF, and VION™ IMS Qtof and other models of high-resolution mass spectrometry. Our research services cover the drug discovery stage from lead compound optimization selection to drug clinical research stage, as well as metabolic product analysis and identification using radioactive isotope tracing. We have supported the completion of over a thousand global application projects, with nearly a hundred clinical metabolite identification projects. We can complete thousands of metabolite identification studies annually.
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Assays
Study Strategies
After the drug enters the human body, the produced metabolites are all exogenous substances for the human body. When the exposure to a metabolite at a steady state exceeds 10% of the total exposures of all drug-related components in human, the safety of this metabolite should be evaluated in toxicological studies. Drug metabolites in plasma can be searched and identified using high-resolution mass spectrometry combined with relevant data processing software, as well as the relative abundances of the detected metabolites. For major metabolites, further comparison of its exposure to human and toxicological species should be determined. Results from the study can help to evaluate if the selected toxicological species are appropriate.
Case Study
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A pooled plasma sample from human after repeated administration of a drug candidate is prepared by an AUC method, and then analyzed by LC-UV/HRMS. As shown in Figure 1 and Table 1, five metabolites are detected, identified and semi-quantitatively determined. Both M4 and M5 account for more than 10% of the exposure of the total drug-related components in human at steady state. Due to no metabolite standards, the peak areas of the human metabolites in the AUC-pooled human and animal plasma samples are compared (Figure 2). Results from the analysis can confirm whether the exposure of high proportion metabolites in toxicological animal species is higher than in human. To avoid matrix interference, blank human and animal plasma were added to real animal and human plasma (Figure 2). The formula in Figure 2 was used to evaluate the exposure of metabolites in human and animal plasma.
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Metabolite profiles of parent drug and its metabolites in human plasma at steady state
Figure 1
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Relative abundance of parent drug and its metabolites in human plasma at steady state
Table 1
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A) Mixed method to overcome matrix effect
Figure 2
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B) Formula for calculation of exposure multiple
Figure 2
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Experience
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10+
Years of experience
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80%
Successfully supported NDA submissions for FDA and NMPA
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10+
MIST studies
Instruments and Software
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Instruments
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Software
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Thermo Orbitrap Eclipse™ Tribrid™
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Thermo Orbitrap Exploris™ 480
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Thermo Q-Exactive™ HF
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Waters VION™ IMS QTof
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Thermo Q-Exactive™
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Thermo Q-Exactive™ Plus
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Therno LTQ Orbitrap XL
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Waters Xevo®G2 QTof
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Solid scintillation counter: off-line detection of radioactivity
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Liquid scintillation counter: total radioactivity detection
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On-line detection of radioactivity
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Thermo Scientific™ Compound Discoverer™
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Thermo Scientific™ Mass Frontier™
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Thermo Scientific™ Metworks™
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Waters MetaboLynxTM
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Mass Analytical Mass-MetaSite
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Waters UNIFI®
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Thermo Scientific™ Biopharma Finder™
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FAQs
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When does MIST study need to be carried out？
When a metabolite (especially Phase I metabolite) in human steady state plasma accounting for more than 10% AUC, it is necessary to compare the exposure of the major metabolite in steady state plasma in human and in toxicological species to evaluate whether the safety of the major metabolite has been adequately assessed or not.
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When is the suitable time for MIST?
MIST studies are conducted during Phase I clinical study MAD stage.
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What samples are used for MIST?
Plasma samples at steady state under clinical therapeutic dose are selected to conduct MIST study. Steady state plasma samples in toxicological species under NOEAL are selected to compare with that in humans.
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