PK-Sim and Specific Clearance

[krinaj]

Hello,

I am trying to understand how biliary elimination processes should be added in PK-Sim if data comes from in vitro studies to put together some IVIVE workflows in #101 . And I want to confirm that I am understanding this correctly.

Let's say I am using data from a paper and description is as follows:

Now, I have from results is PSbile and fu(experiment), and PSbile is actually PSbile_app/fu (as described above). To add this in PK-Sim --> biliary clearance --> Plasma Clearance, I need to add apparent biliary clearance (which will be PSbile*fu) since plasma clearance will be scaled within PK-Sim to get specific clearance by considering protein binding and volume of compartment. Is that understanding correct or am I confused about specific clearance?

Thanks,
Krian

[StephanSchaller]

@msevestre , can we get an IVIVE label we can add to questions?

[msevestre]

done

[StephanSchaller]

@krinaj , that's indeed an interesting paper you have there! Could be interesting to revisit IVIVE results for the listed compounds...!

Regarding your approach I have some doubts, as:

• PK-Sim requires a value for plasma (not intrinsic) clearance (normalized to body weight)
• The fu(hep) from your paper is not the same as the fu (plasma) from PK-Sim, but the intracellular fraction unbound in hepatocytes. In PK-Sim, this corresponds to the "Partition coefficient (Water/Cell)" which is only visible in MoBi...

So I think we need a new biliary clearance "process type" from in-vitro to account for sandwich cultured hepatocytes...

If I am not mistaken, with your data you may now multiply the intrinsic PSbile with the average human hepatocyte volume (average rat hepatocyte volume in your paper was given as 5.2 μL/mg protein) and use this then directly as specific clearance value... (ignoring the above entries in PK-Sim)...?

@Yuri05 , any other experiences here with in-vitro data for biliary clearance?

[krinaj]

Thanks, Stephan. Very helpful comments. The paper you mentioned in comment above is the first one in the series of papers the same authors have. The data I got was from another paper where they used human hepatocytes, but for methods, they referred to their above mentioned first paper. Below is a list of similar papers (I like to refer to the latest one). Pharm Res (2012) 29:603–617 DOI 10.1007/s11095-011-0607-2 Biopharm. Drug Dispos. 33: 179–194 (2012) DOI: 10.1002/bdd.1784 ADMET & DMPK 3(1) (2015) 1-14; doi: 10.5599/admet.3.1.144 https://www.ncbi.nlm.nih.gov/pubmed/26948853 Does "plasma clearance" in biliary clearance process refer to peripheral venous blood plasma clearance or hepatic compartment blood plasma clearance? I think using in vitro biliary clearance scaled to liver volume as specific clearance is a great idea. Actually, I later noticed in Riede et al 2016 paper that ketoconazole fraction metabolized is 100% and biliary clearance is 0% as per calculations, so I don't need to use it for this example. Using only metabolic clearance works beautifully. I will try IVIVE of biliary CL for some other example. Thanks, Krina

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On Wed, May 16, 2018, 4:10 PM esqlabs GmbH ***@***.***> wrote: @krinaj <https://github.com/krinaj> , that's indeed an interesting paper <https://www.ncbi.nlm.nih.gov/pubmed/22011931> you have there! Could be interesting to revisit IVIVE results for the listed compounds...! Regarding your approach I have some doubts, as: - PK-Sim requires a value for plasma (not intrinsic) clearance (normalized to body weight) - The fu(hep) from your paper is not the same as the fu (plasma) from PK-Sim, but the intracellular fraction unbound in hepatocytes. In PK-Sim, this corresponds to the "Partition coefficient (Water/Cell)" which is only visible in MoBi... So I think we need a new biliary clearance "process type" from in-vitro to account for sandwich cultured hepatocytes... If I am not mistaken, with your data you may now multiply the intrinsic PSbile with the average human hepatocyte volume (average rat hepatocyte volume in your paper was given as 5.2 μL/mg protein) and use this then directly as specific clearance value... (ignoring the above entries in PK-Sim)...? @Yuri05 <https://github.com/Yuri05> , any other experiences here with in-vitro data for biliary clearance? — You are receiving this because you were mentioned. Reply to this email directly, view it on GitHub <#176 (comment)>, or mute the thread <https://github.com/notifications/unsubscribe-auth/AUST3cw0CDMtf1O2pADInjV7rBMvQN4zks5tzIfHgaJpZM4T8LAK> .

[msevestre]

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