Simulating Peritoneal Concentration

Phoenix Certara Forums Modelling and Simulation
1

Hello,

We are hoping to develop a graphical model for an orally administered drug. We have access to data which includes plasma concentration and initial parameters but are interested in simulating the peritoneal concentration following oral administration. Is it possible to create a graphical model in Phoenix which will predict peritoneal concentration without any initial Cobs data for the peritoneal compartment? Any ideas on how to do this?

Thank you!

2

Dear Newbie

I thought I answered that one.

here is a project that does what you ask for.

Let me know if you need more clarificaiton.

best Regards

ip_iv_data.phxproj (597 KB)

3

Hi Serge,

Thanks for the reply and for attaching the project file! In the project that you attached there is an initial Aip in the Data set. In our case we only know the dose of the orally administered drug (Aa) and observed concentrations in the plasma. When I alter the value of Aip to zero at time zero the resulting graphs only include data for the plasma concentration and do not include the observed concentration in the peritoneal cavity. Will I be able to use the project you posted in such a way that the observed concentration in the peritoneal cavity will be simulated WITHOUT initial peritoneal dose and observed peritoneal concentration?

Thank you!

4

Dear Newbie

The way the graph has been designed, the drug cannot go from Plasma to the IP area.

If this is not the case then you need to make the graph reflecting that.

My graph will give you no level in the IP area if IP dose=0.

Can you explain all the processes you want to include, then I can help you with the graphical model.

What happens with the drug, where is the dose input and once the drug is given where does it go.

Best

Serge

5

Hi Serge,

Here is a quick description of what we need the model to do. I also attached a diagram to go along with the description.

Thank you in advance for all your help!

What the model needs to represent:

  • Oral administration

  • 400 mg capsule twice daily

  • 3 compartments :

  1. plasma

  2. peritoneal cavity

  3. the rest of the body aside from the plasma and peritoneal cavity

  • the drug is cleared from plasma

What we have:

  • Estimated absorption rate constant between plasma and peritoneal cavity

  • Cobs in the plasma compartment

  • Clearance from the plasma

  • Rate constants

What we want the model to predict:

**The observed concentration in the peritoneal cavity

We hope to be able to model both the predicted peritoneal concentration and the already known plasma concentration simultaneously.

If you could guide me on how to go about accomplishing the following it would be greatly appreciated.

Thank you!

Drug administration diagram.docx (273 KB)

6

Dear colleague

I am attaching 3 potential mdoesl you could use .

I think model 1 is the best.

These models will give you a predicted concentration in the IP area.

The first model I htink is the right one has a extravascular dose input followed by the drug entering the IP area and then absorbed into Plasma. Then the drug is distributed into the peripheral compartment.

It is like given the drug in a compartment, then adding a transit compartment necessary to simulate the drug entering the IP compartment and then absorption.

Let me know if it helps.

best

Serge

oral_ip_plasma.phxproj (204 KB)

7

Hi Serge, thank you for the attachments!

I tried using the first model that you attached, but unfortunately I am still not able to predict the concentration in the IP area.

When I import my data set (which only has observed concentrations in the plasma compartment) I am able to map the variables in the set up menu but then when I execute the model only one concentration graph (CObspl vs.t) is generated.

The CObspe vs. t graph is missing from the results, and this is the graph we need in order to obtain the predicted values.

Any idea on what I am doing wrong?

Thank you!

8

Dear colleague

I need to see your project. If it si confidential, please chan ge the names ut simulation only should not be a problem wth respect to confidentiality.

Only cone I see your project I can debug it.

the model I sent you would give predicted concentration if the drug is given orally and you ask for a table using add/sim table option.

Please send me the project and I will resolve the problem.

best Regards

Serge

9

Dear Newbie

I think I have an idea what happens and may be I have the solution.

First I check about IP and base on my colleague Oral drug would go to Plasma and then exchange with IP.

Then a better model would be extravascular compt with dose input, then absorption into Plasma and from Plasma exchange with IP and all other tissues (4 compartments total).

Now I think you forgot to put a two way flow from Plasma to IP which would explain no prediction in IP if you were unlucky and the one way flow was from IP to Plasma and not Plasma to IP.

Anyway the model I made works. YOU get both IP and Plasma predictions and the fit is good.Let me know if all is clear now.

best

Serge

oral_dose_ip_plasma_obs.phxproj (1.19 MB)

10

Hi Serge!

I tried using the last model you sent over and it does work! Everything was very clear and the model fits well.

Thank you so much for all of your help! We really appreciate it!

11

Iam attaching data again as it did not upload properly

Thanks
Harish

data.xlsx (8.29 KB)

12

I cannot understand what you wrote about the PK parameters.

Send me the model in terms of differential equations and a table with the parameter names as in the model and their values.

Best would be to send me the project . If it is confidential, send me the project with the input data set deleted.

Without that I cannot help you.

best

Serge

13

Hi Serge,

Iam attaching the PHX file, my drug is given IV bolus at 270mg/m2, I need the Peritoneum concentrations predicted

Iam also attaching the 3 comp PK parameters of the drug for your ready reckoner

Hope it helps

Regards

Harish

PTX IV project.phxproj (34.2 KB)IV PK param.xlsx (8.05 KB)

14

Dear Harish

What compartment number is the peritoneum? Is it compartment 2(V2,Cl2) or compartment 3(V3,Cl3)?

Now what prediction do you want. What dosing regimen(dose, route, dosage interval,etc.)

Best

Serge

15

Hi Serge,

drug follows 3 comp model, i donot have the peritnoeum concnetrations so i will have to predict peritnoeum concentrations post IV bolus dosing of the drug 260mg/m2 is the dose

hope it helps

Regards

Harish

16

Dear Harish

You can predict peritoneum concentrations only if you do the following:

1: you have observed data in peritoneum and eventually in Plasma

2: You fit the model using the template I gave you

1 compartment is the oral compartment linked to plasma

another compartment is the Plasma compartment

another compartment is the peritoneum compartment

the last compartment is all other organs we call the peripheral compartment.

Now the graph looks like a 3 compartment model with oral input (4 compartments together)

Now if you want to predict peritoneum concentrations, you need t put names of your volumes and clearance.

Let say that V is the volume of the central and its clearance is Cl

Let us say that V2 and Cl2 are the volume of the peritoneum and the inter_compartmental clearance Plasma to Peritoneum

Let us say that V3 and Cl3 are the volume and inter_compartmental clearances Plasma to all other organs, then you can predict peritoneum concentrations

You cannot predict peritoneum concentrations if you get general information about the PK of the drug which follows a 3 compartment model.

Only if you have the data and fit the model tot he data as I told you.

If you did that , then you know if V,V2 or V3 is the volume for peritoneum, same for Clearance.

best Regards

Serge