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Metabolite Bioanalysis

Metabolite Bioanalysis in Drug Development: Recommendations from the IQ Consortium Metabolite Bioanalysis Working Group

A Metabolite Bioanalysis Working Group composed of experts from 14 different pharma companies have proposed recommendations around best practice in metabolite bioanalysis during drug development. The proposals are particularly relevant to human circulating metabolites arising from the multiple ascending dose study in First-In-Human (FIH) trials and beyond.

Case studies are included to illustrate how fit-for-purpose and stage-appropriate LC-MS BA methods can help address challenges associated with active metabolites, MIST-related metabolites, DDI aspects of a metabolite(s) and/or chiral metabolites, to support development projects.

Survey results

Results from respondents of a cross industry survey among the 29 member companies about metabolite bioanalysis practices include:

  • ~80% begin quantifying pharmacologically active metabolite(s) based on the potency (in vitro or in vivo) of the metabolite and stop quantifying such metabolite(s) based on the in vivo exposure in combination with the PD effect of the metabolite relative to parent drug.
  • >33% quantitatively analyse pharmacologically inactive metabolites to address program-specific concerns and/or regulatory inquiries on a case-by-case basis. For instance, if metabolic clearance occurs through a single CYP affected by inhibition or induction.
  • ~66% use an animal/human metabolite ratio of 0.5 or higher to establish coverage, while a smaller portion (~20%) of the respondents utilize a ratio of 1 or higher, depending on the methodology employed in generating the ratio values.
  • > 90% do not use fully validated methods as per the Health Authority (HA) guidelines on bioanalysis method validation. The term “validated” in this instance is not considered the same as validation related to regulated studies in HA guidelines. Instead, the use of a well characterised fit-for-purpose assay is recommended.
  • In nonclinical development, >70% use qualified bioanalysis (BA) methods for non-GLP quantification of metabolite(s), and >80% agreed that a fully validated BA method should be implemented for quantification of active metabolite(s) for compliance when supporting GLP toxicity studies.
  • Through clinical development, >70% validate the bioanalysis method for any metabolite(s) of interest, whilst 30% use exploratory or qualified methods to aid in understanding metabolite exposure or demonstrate appropriate coverage.
  • > 50% validated the BA method for metabolite concentration data as part of Phase II trials with 30% doing so during Phase III trials.

 

Paper

Li, W., Vazvaei-Smith, F., Dear, G., Boer, J., Cuyckens, F., Fraier, D., Liang, Y., Lu, D., Mangus, H., Moliner, P., Pedersen, M.L., Romeo, A.A., Spracklin, D.K., Wagner, D.S., Winter, S. and Xu, X. (2023), Metabolite Bioanalysis in Drug Development: Recommendations from the IQ Consortium Metabolite Bioanalysis Working Group. Clin Pharmacol Ther. Accepted Author Manuscript. https://doi.org/10.1002/cpt.314

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