While there were arguably no big surprises, it was most encouraging to see several themes that have been championed by our Evotec colleagues (amongst others) have been incorporated into the new FDA DDI guidelines: the consideration of unbound exposure (Cmax) for risk analyses; an update on static models ; recognition that the HepaRG cell line can indeed be a useful test system for CYP induction. A recent summary of these key developments can be found here: http://www.tandfonline.com/doi/abs/10.1517/17425255.2015.1013095?journalCode=iemt20. As expected, the revised draft from the FDA now brings the recommendations closer in line with the EMA guidance released back in 2012.
In this blog article, we focus on CYP induction, and highlight the key changes to the FDA guidance. Perhaps one of the most interesting changes in this respect relates to the acknowledgement of some immortalised cell lines as an acceptable approach for CYP induction. This may well lead to a surge in testing in the hepatic cell line, HepaRG, which has been shown to be a useful model for assessing induction. It is unlikely that this would, at least in the short term, replace testing in multiple human hepatocyte donors but it may be a viable substitute for at least one of these donors early in drug discovery.
Catalytic activity has also made a return to the guidance document as a possible alternative for mRNA with the caveat that induction may be masked by time-dependent inhibition (TDI) effects. Despite this, we expect that mRNA will maintain its popularity as the preferred endpoint for CYP induction but catalytic activity alone may be used if previous knowledge and testing of the compound suggests that inhibition is not an issue. The new draft guidance is also now aligned with the EMA guidance in terms of measuring the test compound concentration in the medium at several time points on the last day of the incubation.
A wider number of data analysis options are now presented for CYP induction – these include approaches such as a fold-change approach, correlation models (including using relative induction score (RIS) and Imax/EC50 values) as well as a basic R3 model. The equation for R3 also now takes into consideration 10 x the maximum unbound Cmax of the interacting drug rather than the total Cmax value.
To keep you up to date with all the current regulatory guidance for in vitro DDI studies, we have revised our popular booklets: ‘Everything you need to know about ADME’ and ‘DDI regulatory guidance – An easy to follow guide’. You can download the latest version of our guides from our website. Alternatively, why not order a hardcopy so you have it handy at your desk for future reference.