Dear Jhohann Benzi

You should trace all active metabolites of your drug. You can make a validated analytical method for detecting and quantifying of the metabolites in the serum samples. Then obtained the concentration-time details. After this, you can calculate the Clearance and distribution volume or other PK parameter.

Best regards

If you've not seen Phoenix's visual model builder then you may want to look at that; in our free forum we have links to several videos and tips that should help you if you have access to this tool;

https://support.certara.com/forums/topic/928-lesson-2-parent-and-metabolite-kinetics/

Simon

Dear Saleh Rakhshani,

Thank you for your answer.

Dear Simon AA Davis,

The link provided by you has exactly what I was looking for. Thank you so much.

Dear Jhohann Benzi ,

I hope that by this time you have a working metabolite model. If you are still trying out things, you could also make use of this publication (https://www.ncbi.nlm.nih.gov/pubmed/26332855) and the possible metabolite parameterizations that they present in appendix 2.

In short, you have two options: (1) calculate apparent values for the distribution volume and elimination of your metabolites or (2) make your model identifiable by making assumptions on the PK of the metabolites (either on the fraction of drug metabolized or the metabolite formation clearance, metabolite distribution volume or elimination clearance).

Just keep in mind that the assumptions you make should rely on literature (not sure if this is available?) and also that the assumptions for the parameters describing the PK of the metabolites will directly influence your parameter estimates (e.g. from the Ahlers et al 2015 paper: if you assume a higher value for the metabolite clearance than the true value then the values for the fraction metabolized and metabolite Vd will also be higher).

Hope this helps.