Non linear Protein Binding Function in PK-Sim/Mobi

[hardik1chandasana]

Hello Everyone,

I am working on a compound which has nonlinear protein binding in human plasma at a therapeutic concentration.

I would like to know how to add concentration-dependent protein binding (Saturation in plasma and tissue) in PK-Sim/Mobi.

Thanks

[prvmalik]

I believe you can do this by setting fraction unbound to 1 in your compound description and instead doing the protein binding manually. Add a "protein binding partner," specify the kon and koff binding rate constants and have it present in plasma and tissue at saturable concentrations.

[msevestre]

@prvmalik What about partition coefficients? I fear that their calculation is dependent on fu value.

[StephanSchaller]

What about partition coefficients? I fear that their calculation is dependent on fu value.

Yes, this is especially relevant if you have a small molecule with intracellular exposure.

For proteins, solution as proposed by @prvmalik might almost work, except that if you define an explicit protein binding partner you also need to consider that protein binding partners defined this way do not distribute (as albumin does).

But exporting to MoBi and defining fu as a formula dependent parameter instead as a constant may work... Maybe this could be a feature request for PK-Sim?

[hardik1chandasana]

Thank you all for the suggestions.

The molecule is small molecule Mol wit <600 Da. I wanted to simulate plasma exposure and interstitial exposure not intracellular.

The nonlinear PPB is clinically relevant.
@StephanSchaller Could you please suggest me any reading materials where this process ( exporting to Mobi and equation writing) is described for PPB?

I have Kd and Bmax in the human plasma.

Is it possible to apply the same non-linearity in tissues as well? Although I don’t have tissue binding data.

[StephanSchaller]

I'll get back to you in the next 5 days. If not, please remind me by writing here.

[hardik1chandasana]

@StephanSchaller I will remind you. Thanks

[hardik1chandasana]

@StephanSchaller Gentle reminder about non-linear PPB function.

[StephanSchaller]

Sorry, I am quite swamped at the moment, so a short guide will have to do:

Basically, once you have set up your simulation in PKSim you export it to MoBi by "right-click" on the simulation and selecting -> "export to MoBi" in the drop-down menu.

The simulation will appear in MoBi and you can then edit the "fu" directly:

• Browse to your Building Blocks and double click on the Molecule Building Block (will have the sam name as your simulation)
• On the right, a window will appear with a list of all your molecules in the simulation. Select (double click) the one for which you ant to change the fu.
• Again, further to the right you will see two tabs with one named "Parameters". Select this one and browse to the parameter "Fraction unbound (plasma, reference value)".
• There under "Value" change (with drop-down menu) from "Constant" to "Formula"
• Enter the formula you want to use to describe your observed nonlinearity (please refer to the help menu ( the question mark on the very top right of the MoBi window) on how to create a formula
• recreate your simulation --> run (also here the help menu may help)

[hardik1chandasana]

@StephanSchaller Thanks for the explanation. I will try and ask you if any help needed.

[msevestre]

@hardik1chandasana Please let us know if you have any more questions. Cheers