Skip to main content
SpringerLink
Log in

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

  • Meeting Report
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Baillie TA, Cayen MN, Fouda H, Gerson RJ, Green JD, Grossman SJ, et al. Drug metabolites in safety testing. Toxicol Appl Pharmacol. 2002;182:188–96.

    Article  PubMed  CAS  Google Scholar 

  2. Hastings KL, El-Hage J, Jacobs A, Leighton J, Morse D, Osterberg RE. Letter to editor. Toxicol Appl Pharmacol. 2003;190:91–2.

    Article  PubMed  CAS  Google Scholar 

  3. Smith DA, Obach RS. Metabolites and safety: what are the concerns, and how should we address them? Chem Res Toxicol. 2006;19:1570–9.

    Article  PubMed  CAS  Google Scholar 

  4. Timmerman P, Kall MA, Gordon B, Laakso S, Freisleben A, Hucker R. Best practices in a tiered approach to metabolite quantification: views and recommendations of the European Bioanalytical Forum. Bioanalysis. 2010;2:1185–94.

    Article  PubMed  Google Scholar 

  5. Yu CP et al. A rapid method for quantitatively estimating metabolites in human plasma in the absence of synthetic standards using a combination of LC/MS and radiometric detection. Rapid Commun Mass Spectrom. 2007;21:497–502.

    Article  PubMed  CAS  Google Scholar 

  6. Yi P, Luffer-Atlas D. A radiocalibration method with pseudo internal standard to estimate circulating metabolite concentrations. Bioanalysis. 2010;2:1195–210.

    Article  PubMed  CAS  Google Scholar 

  7. Zhang D, Raghavan N, Chando T, Gambardella J, Fu Y, Zhang D, et al. Humphreys WG LC-MS/MS-based approach for obtaining exposure estimates of metabolites in early clinical trials using radioactive metabolites as reference standards. Drug Metab Lett. 2007;1:293–8.

    Article  PubMed  CAS  Google Scholar 

  8. Vishwanathan K, Babalola K, Wang J, Espina R, Yu L, Adedoyin A, 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. Chem Res Toxicol. 2009;22:311–22.

    Article  PubMed  CAS  Google Scholar 

  9. Walker GS, Ryder TF, Sharma R, Smith EB, Freund A. Validation of isolated metabolites from drug metabolism studies as analytical standards by quantitative NMR. Drug Metabolism and Disposition. 2011;39(3):433–40.

    Article  PubMed  CAS  Google Scholar 

  10. Gao H, Deng S, Obach RS. A simple liquid chromatography-tandem mass spectrometry method to determine relative plasma exposures of drug metabolites across species for metabolite safety assessments. Drug Metab Dispos. 2010;38(12):2147–56.

    Article  PubMed  CAS  Google Scholar 

  11. Ma S, Li Z, Lee K-J, Chowdhury SK. Determination of exposure multiples of human metabolites for MIST assessment in preclinical safety species without using reference standards or radiolabeled compounds. Chem Res Toxicol. 2010;23(12):1871–3.

    Article  PubMed  CAS  Google Scholar 

  12. ICH M3(R2). 2010. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065006.htm. Accessed April 2013.

  13. Gao H, Obach RS. A simple liquid chromatography-tandem mass spectrometry method to determine relative plasma exposures of drug metabolites across species for metabolite safety assessments. II. Application to unstable metabolites. Drug Metab Dispos. 2012;40(7):1290–6.

    Article  PubMed  CAS  Google Scholar 

  14. Espina R, Yu L, Wang J, Tong Z, Vashishtha S, Talaat R, et al. Nuclear magnetic resonance spectroscopy as a quantitative tool to determine the concentrations of biologically produced metabolites: implications in metabolites in safety testing. Chem Res Toxicol. 2008;22:299.

    Article  Google Scholar 

  15. Guidance for industry: bioanalytical method validation. 2001. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070107.pdf. Accessed June 2013.

  16. Gao H, Obach RS. Addressing MIST (metabolites in safety testing): bioanalytical approaches to address metabolite exposures in humans and animals. Curr Drug Metab. 2011;12(6):578–86.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the efforts of Dr. Debra R. Luffer-Atlas in helping moderate the discussion at the symposium and editing this summary. The authors would like to thank PPDM and CPTR sections for sponsoring our symposium at 2012 AAPS annual meeting.

Disclaimer

The views expressed are those of the authors and do not reflect official policy of the FDA.

No official endorsement by the FDA is intended or should be inferred.

Author information

Authors and Affiliations

  1. Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut, 06340, USA

    Hongying Gao & R. Scott Obach

  2. Office of New Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland, USA

    Abigail Jacobs

  3. DMPK Science and Technology, XenoBiotic Laboratories, Inc., Plainsboro, New Jersey, USA

    Ronald E. White

  4. OTS\OCP\DCP V, Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland, USA

    Brian P. Booth

Authors
  1. Hongying Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abigail Jacobs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald E. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian P. Booth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Scott Obach
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongying Gao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gao, H., Jacobs, A., White, R.E. et al. Meeting Report: Metabolites in Safety Testing (MIST) Symposium—Safety Assessment of Human Metabolites: What’s REALLY Necessary to Ascertain Exposure Coverage in Safety Tests?. AAPS J 15, 970–973 (2013). https://doi.org/10.1208/s12248-013-9502-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-013-9502-6

Key words

Search

Navigation