The Fraction absorbed value was exceed 1 when it was simulated using EHC parameters.

[hjhj112233]

Dear community,

I have PK observed data which has double peak. So I optimized many parameters such as EHC, gallbladder, transporters, biliary clearance and meal...… and then I made double peak simulation.

Simulated PK parameters (Cmax, AUC…) fitted well with it’s observed data. But I wonder why Fraction absorbed was over 1. My Fraction absorbed value was 2.11 and I think it is impossible to make sense. The PK-sim manual said that "Absorbed fraction of applied oral dose. Please note that, e.g. in the case of enterohepatic circulation, this fraction may exceed 1".

Is it just limitation of PK-sim?
Please share your opinions.... Thanks

[tobiasK2001]

Hi, Sorry for answering so late.
But I don't think your fraction absorbed of 2.11 is a limitation of PK-Sim. It just tells you that your compound molecules are absorbed more than once due to your EHC assumption. And it is quite physiological to assume that in case of enterohepatic cycling you have a reuptake of excreted compound. It might prompt you to think about your assumption. I am not sure if EHC has been found for Glipizide? Is your compound a substrate for bilary transporters?
You might think of other possible explanation for double peaks. E.g. check this out https://doi.org/10.1208/s12248-020-00548-8 and look at figure 3. Nefadozone-HCl. Pepin et al could rule out EHC and discuss two other possibilities coming from the absorption side:
A) Since both nefazodone-HCl solubility and permeability are high, this drug could be a marker of gastric emptying and partial gastric emptying has been reported for other products in the literature.
(B) Wettability issues and consequently slow dissolution rates are reported for nefazodone-HCl tablets, despite the high measured equilibrium solubility.

Hope that might help you.

Best, Tobias