Best Practices in a Tiered Approach to Metabolite Quantification: Views and Recommendations of The European Bioanalysis Forum

Abstract

The relationship between the exposure to drug metabolites and overall drug safety has become an integral part of the drug-development process. In-depth discussions in the scientific community, as well as recent guidelines on Drug Safety Testing of Metabolites from the US FDA (often referred to as the MIST guidance and ICH M3(R2) from the International Conference on Harmonization (ICH), has brought clarity to the regulatory requirements of the sponsor company in providing documentation on circulating levels of qualifying metabolites. However, less attention has been given to the challenges now faced by the bioanalytical community in supporting these new guidance policies. In this paper, the European Bioanalysis Forum (EBF) is providing a recommendation on which quality standards to apply when assessing the (relative) abundance or absolute concentrations of metabolites. This paper is the result of both an intensive consultation within the EBF (through internal surveys amongst EBF member companies and discussions) and consultation of the broader bioanalytical community (through discussions at international conferences). These recommendations will provide an increased understanding of how to apply a tiered approach to metabolite quantification as part of the bioanalytical strategy. As such, it aims to provide support to the bioanalytical community on the appropriate level of validation required at each stage of the drug-development process.

Systemic Exposure to the Metabolites of Lesogaberan in Humans and Animals: A Case Study of Metabolites in Safety Testing

“…The routes to formation of the more surprising defluorinated and guanidino metabolites have previously been discussed (Ekdahl et al, 2013). Bioanalytic methods were subsequently developed and qualified for the determination of metabolite concentration in human and animal plasma samples (Dunér et al, 2013), which is in accordance with the "tiered approach" recommended by the European Bioanalytical Forum (Timmerman et al, 2010): preliminary screening to detect metabolites, followed by the development and use of qualified and/or validated bioanalytic methods to determine absolute parent compound and metabolite exposures.…”

Giving Consideration to Scientific Validation in Japanese Drug Application by Japan Bioanalysis Forum Discussion Group

“…With regard to metabolite in plasma, a TA was discussed in the Global Bioanalysis Consortium [8] as well as the EBF [1,9], and described in the MHLW BMV guideline [10], and our previous DG (DG2014-09) also discussed and published it [4], however urine and tissue has been less discussed. Assay-appropriate SV may p rovide basic ideas for evaluation in these areas.…”

Development of analytical methods for the quantification of metabolites of lesogaberan in a MIST investigation

“…During the preclinical phase and first-in human studies, the EBF recommends the use of qualified methods for metabolites with anticipated low or unknown contributions to the pharmacological activity or toxicity. Thus, in these cases the methods used do not need to be fully validated (Timmerman et al, 2010;Smith, 2011).…”