Dear all,
Following the FDA guidance (attached file), safety of metabolites should be tested depending of its exposure at the steady state in human.
"Human metabolites that can raise a safety concern are those formed at greater than 10 percent of total drug-related exposure at steady state".
My concern is about the calculation of metabolic and total drug exposure. Should I use AUC0-24h ? AUClast ? AUCinf ? Should I consider the half-life of the analytes to choose the best AUC ?
Results can differ a lot depending on what kind of AUC I use.
Thank you for your help
Benoit
After a single dose, my preference goes to AUCinf because it represents the total exposure (with all the caveats to have long enough sampling to get a good estimate of AUCinf for both parent and metabolites). In practice, AUClast is usually also used. If the results are different, you need to understand and explain why. At steady state after multiple dosing, use the AUC0-24h (although you can use AUC over a dosage interval, if less than 24 h, assuming or knowing that there is no substantial diurnal variation).
Thank you so much Rene for your kind answer.
At steady state, I've got a huge difference between AUC0-24h and AUCinf mainly due to a long half-life. As a result, the % of extrapolation between AUC0-24h and AUCinf is huge also. As a result, I would consider my AUC0-24h as no relevant for my compound. Thus, I envisage to use onfly AUCinf from PK studies with sufficient time points to cover the terminal phase of my PK.
It will allow me to have a lower metabolite exposure to total drug exposure (
Benoit, Please note that at SS, AUCinf is not a meaningful parameter; it should be used only for single-dose data (it will overestimate exposure and is really not appropriate at SS). As Rene mentioned, at SS, use AUCtau (ie, the dosing interval) or AUC0-24 if applicable.
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