Oral Dose Not Exhibiting Absorption​/Bioavaila​bility in Simulation

Hello! I am trying to use this model "Estimating the Bioavailibility of a Drug" that I found here, to do a simultaneous fitting of my IV infusion and P.O. blood concentration time profile. I implemented a two compartment model as well. For some reason, when I am running a simulation the oral dose exhibits a bioavailbility of >= 1, even though I have the parameter F set as 0.2. I attached images of my simulation curve (green is oral dose), model diagram, ODEs, and dosing setup. I'm thinking it might have something to do with the way I set up the dosing, but please let me know if you have any advice on how I should troubleshoot this. I am using R2024a. Please let me know if I should include anything else. Thanks!

[Arthur Goldsipe]

Could you attach your (sbproj) project file? That would make it much easier for me to investigate the issue.

[Arthur Goldsipe]

Oh, and if you aren't comfortable sharing your project here publicly, feel free to send it to me privately. :-)

[grace]

I will attach it here, thank you so much!

[Arthur Goldsipe]

Thanks. I downloaded and opened the file, but now I realize I don't really understand the problem or how to reproduce it. I can't figure out how to reproduce the plot from the PDF. When I simulate the model, my plots don't look like your PDF. And I also don't know what you're looking at in the plot that tells you that bioavailability is more than 1. Are you pointing out that the green curve starts with a value of 4.5x10^5? What species does that represent?

I do think something is wrong with the attached model though. I see that the PO dose is applied to Adepot. But then nothing happens to it after that. (The only usage of Adepot is in an initial assignment rule, and that takes place just before the simulation is applied.)

[grace]

Thank you so much for your reply!

Yes, sorry if my explanation wasn't clear, I meant to say that since the green curve starts with a value of 4.5 x10^5, which is the exact value of the oral dose, the F and ka values aren't being incorporated into the differential equation somehow since that means the bioavailibility would be 100%. The green curve represents the GI_Compartment.Drug_Oral species. I got rid of the Adepot species just for simplicity, and applied the PO dose to GI_Compartment.Drug_Oral species. I have also uploaded the dataset I am using to the Model Analyzer, and will attach the project with the updates mentioned. I'm wondering if this might have to do with the initial assignments? I will continue to troubleshoot. Thank you so much for your help!

[Arthur Goldsipe]

I will look at this tomorrow, unless someone else figured it out before then.

[grace]

Sounds good, thank you a lot Arthur!

[grace]

Just wanted to update that I figured out a solution to the problem! I ended up creating a new species called Drug_Infusion in the Blood compartment and assigning the Infusion dose to that species. Then i used the Drug_Central in the Blood compartment for simulation of the oral dose, and Drug_infusion for the simulation of the Infusion dose. It ended up solving the issue I was having with the starting value of the oral dose being 4.5x10^5! Thanks a lot for your help.

[Arthur Goldsipe]

Excellent. I'm just going to copy that into the answers section, so that it's clear this question has been answered.

Answer 1

[Arthur Goldsipe]

Copying the answer from the comments: "Just wanted to update that I figured out a solution to the problem! I ended up creating a new species called Drug_Infusion in the Blood compartment and assigning the Infusion dose to that species. Then i used the Drug_Central in the Blood compartment for simulation of the oral dose, and Drug_infusion for the simulation of the Infusion dose. It ended up solving the issue I was having with the starting value of the oral dose being 4.5x10^5! Thanks a lot for your help."