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.
References
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.
Hastings KL, El-Hage J, Jacobs A, Leighton J, Morse D, Osterberg RE. Letter to editor. Toxicol Appl Pharmacol. 2003;190:91–2.
Smith DA, Obach RS. Metabolites and safety: what are the concerns, and how should we address them? Chem Res Toxicol. 2006;19:1570–9.
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.
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.
Yi P, Luffer-Atlas D. A radiocalibration method with pseudo internal standard to estimate circulating metabolite concentrations. Bioanalysis. 2010;2:1195–210.
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.
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.
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.
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.
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.
ICH M3(R2). 2010. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065006.htm. Accessed April 2013.
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.
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.
Guidance for industry: bioanalytical method validation. 2001. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070107.pdf. Accessed June 2013.
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.
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
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12248-013-9502-6