Anyone how has worked with SimCyp to simulate time-dependent inhibition (TDI) and investigate the intestinal contribution (inhibition of intestinal CYP) to the overall change in exposure (AUC)?
I want to simulate the clinical outcome of TDI on CYP3A4/5 and also investigate and distinguish between the intestinal contribution (first-pass gut metabolism) and the hepatic contribution (first-pass hepatic metabolism + hepatic elimination clearance) to overall change in exposure of a victim drug.
Is it possible to use the built-in CYP3A4/midasolam model in SimCyp to explore these things? Can this model be used to evaluate the intestinal contribution to the AUC ratio following TDI?
Hi Therese, typically SimCYP have in the past provided support directly and this forum has only been for the Phoenix suite however I’m discussing with my colleagues in Sheffield if a couple of SimCYP dedicated forums would be beneficial on here.
In the meantime Masoud kindly gave me the following to pass on to you;
Assuming the “PK/PD Profile” mode is selected; if the ADAM model is selected for the substrate then in the “Overall Fa Fg” worksheet the Fg (fraction escaped metabolism in the gut) with and without interaction (in this case TDI) are given. The ratio of these two values gives the impact of first pass gut metabolism inhibition on the overall AUC. Of course the overall change in AUC is reported on the AUC worksheets. Given the non-linear nature of TDI it isn’t possible to obtain the Fh changes unless the user selects the “PK/PD Parameters” mode where the static calculations are used to calculate both Fg and Fh with and without interaction and the impact of each can be identified. This is one of the workshop exercise in the Simcyp full workshop.
We hope this brief response helps, I appreciate it may need few iterations; so please reply with further questioins or you may want to directly contact them directly; http://www.certara.com/support
Thank you Simon for your reply and help. I did not know that this forum was only for the Phoenix suite, but I agree with you that a SimCYP dedicated forum would be beneficial on here as well.