During drug development, also the safety of drug metabolites should be considered early enough to avoid massive delays in the progress of the project. There are few important things to keep in mind when investigating the safety of human metabolites, and Admescope’s Head of Safely Metabolism Dr Johanna Haglund will highlight these.
MIST from the…
…authority perspective: It is well established through the regulatory guidelines how the safety of drug metabolites, in addition to the safety of the drug itself, must be demonstrated before a drug is considered for marketing approval by regulatory agencies (FDA 2008, 2016; ICH 2009, 2012; EMA 2012).
…project perspective: Make sure plasma samples from repeated dose studies in man and safety animal species are continuously collected and stored for their use in MIST analysis and evaluation.
…Admescope perspective: Share experience and knowledge in the field, advice on the best direction and analytical approach of each particular project as well as performance of each step utilising the tools described below at every stage from preclinical drug development and further on until to market
It is all about the fate of the drug in the human body. The establishment of the human metabolite profile in plasma (circulating metabolites), supported by additional information from urine and lastly also in feces (hADME), is a crucial step in MIST evaluation. It allows the investigation whether relevant human metabolites have been adequately formed in safety animals and thereby can be considered as safety tested.
The way to final judgment of having or not having a MIST issue is a multistep procedure, tailor-made for each project, although the exposure comparison per se without absolute quantification, is one of the most important steps and required more or less for all projects.
Despite the well outlined MIST evaluation path I am confident to say all projects are unique. We see MIST work as utilisation of a toolbox containing performance of certain required analyses/studies but also other pragmatic approaches to early increase confidence in having or not having a MIST issue.
The required analyses are: Cross-species comparison, MIST exposure comparison including human Met ID (repeated dose studies) and human ADME Met ID (single dose, radiolabelled).
Additional pragmatic approaches comprise: Establishment of response factors if references of metabolites of interest are available, RAM-MS (radioactivity monitoring-MS) response factor if radiolabelled compound is available, inclusion of patient population or elderly that might have different metabolite profiles for several reasons and/or addition of MetID already in the single ascending dose study to establish human metabolite profile early on or as a complement if repeated dose studies comprise low doses.
Written by Johanna Haglund
