Director Novartis Institutes for BioMedical Research, Inc. East Hanover, New Jersey
Within pharmaceutical industry, the project teams for developing safe new drugs are often challenged by the questions related to drug metabolites, which could be active (efficacious or toxic) and/or human unique/disproportionate. These questions include but are not limited to: Which metabolites should be monitored? If so, should they be monitored in preclinical studies or clinical studies or both? If a metabolite needs to be measured, what scientific and quality rigor should be applied to the respective bioanalytical method to fit for the study purpose? Whether there is metabolite(s), among the many from a drug candidate that warrants further investigation for potential risk? To ensure that adequate information on metabolite identity and exposure are available for drug registration, given the inherent complexity of drug development and the need to manage the large portfolios with limited resources, stage-appropriate (or phase-appropriate) approaches have been the trend in the pharmaceutical industry in drug metabolite assessment. By this strategy, different levels of scientific and quality rigor are employed for the metabolite bioanalysis in different types of studies. Depending on the stage/phase of the drug development and the intent of the study, the approach of metabolite bioanalysis is customized to address unique challenges that may arise during these stages/phases, beginning early in the preclinical development and proceeding through First-in-Human (FIH)/First-in-Patient (FIP) studies, Proof-of-Concept (PoC) study, human ADME study and beyond. Such an approach not only helps manage limited research capacity but also ensures that important metabolite(s) is identified and its exposure/safety coverage is established as early as possible to prevent unplanned excursions later in drug development. In practice, in addition to monitoring already known active metabolite(s) of a drug candidate early on in preclinical and/or clinical studies, efforts should be focused on obtaining the maximum amount of metabolite information from studies in early development where non-radiolabeled drug is used. In these studies, individual or pooled study samples from preclinical toxicokinetic and FIH/FIP studies can be analyzed to assess metabolite exposure using exploratory methods. This allows for identification of potential human unique/disproportionate metabolite(s). The outcomes of the human vs. animal metabolite exposure comparison might trigger human ADME study with radiolabeled drug candidate earlier than usual in order to confirm the identity and exposure of the metabolite(s) of interest. If the exposure of the concerned metabolite(s) is found not being covered in the already conducted preclinical studies, steps should be taken to assess the exposure of the metabolite(s) in an additional preclinical study in the already tested species or in a third or fourth species using qualified or validated bioanalytical method. Once confirmed as human unique/disproportionate metabolite(s), a rigor route should be taken to synthesis and certify the concerned metabolite(s) followed by bioanalytical method development and validation in support of metabolite(s) measurement in regulated preclinical safety testing (MIST).
When and how metabolite(s) should be measured in different phases of drug development?
Fit-for-purpose LC-MS methods and the associated scientific and quality rigor for metabolite bioanalysis.
Human unique/disproportionate metabolites
Metabolite exposure coverage
Stability is an important aspect of metabolite bioanalysis