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Plasma clearance parameter #281

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teutonicod opened this Issue Feb 4, 2019 · 7 comments

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teutonicod commented Feb 4, 2019

Dear all,

In the unspecified liver clearance process in PK-Sim, the intrinsic clearance for the liver is calculated using several parameters, one of them being referred to as Plasma clearance. Do you know how this parameter is defined? In a simple model (IV bolus and only unspecified clearance) the value for this Plasma clearance does not coincide with the Total body clearance in the PK-Analysis section, do you have an explanation for the difference of these parameters?
Thanks you in advance for your help!

Best regards,

Donato

@msevestre msevestre added the question label Feb 4, 2019

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msevestre commented Feb 4, 2019

Hi @teutonicod,

The plasma clearance is as far as I can tell from your description the input parameter from the clearance process. e.g. this is what the user enters in the system. PK-Sim then calculates, using a well-stirred model, the specific clearance. see here for details

In order to calculate the Plasma clearance in the PK-Analysis section, PK-Sim uses the last 10% of the curve. Please make sure you have simulated long enough. My suggestion would be to increase your simulation time and then check to see if the values are similar

Hope that helps

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teutonicod commented Feb 4, 2019

Hi @msevestre !
Thanks for your reply! I tried but I still get two different values. I created a dummy project, so I can share it if needed, for now I have included the screenshots of the parameters.

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msevestre commented Feb 4, 2019

@teutonicod Can you try with a 30 min infusion?
CL is calculated using AUCInf and most of the AUC comes from the bolus at the beginning.

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Christoph27 commented Feb 6, 2019

I don't expect that the two plasma clearances are exactly equal. As Michael wrote, the input parameter "plasma clearance" is converted to an intrinsic clearance assuming a well stirred model (cf. e.g. "Yang, J., et al., Drug Metabolism and Disposition 35.3 (2007): 501-502." for the equation used and a discussion of the assumptions). This intrinsic clearance is then used in a PBPK model and the resulting total plasma clearance is different depending on compound properties and if the clearance is high or low.

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teutonicod commented Feb 6, 2019

Thank you vary much @Christoph27 and @msevestre for your answers!

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Christoph27 commented Feb 6, 2019

If I look at the current implementation, there seems to be additionally something else than the above mentioned difference between PBPK and well stirred assumptions: If you add a "Total Hepatic Clearance" process, the clearance rate contains a factor of ~ 1.5 µmol/L corresponding to the concentration of an undefined liver enzyme. However, when CL/[Enzyme] is calculated, an enzyme concentration of 1 µmol/L is assumed. Thus it seems that currently the used CL/[Enzyme] is too high by a factor of ~ 1.5 relative to the given input parameter "plasma clearance" for a "Total Hepatic Clearance" process.
It seems that the factor ~1.5 was introduced in order to get the same total plasma clearance with the same specific intrinsic clearance regardless of using a "Total Hepatic Clearance" process or a clearance process with a metabolizing enzyme.

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sfrechen commented Feb 12, 2019

The retrograde calculation from plasma clearance to specific clearance corrects for f_cell of the liver(fraction intracellular):
CLspec = CL_pls * BW * (Q_liv+Q_pve) / (fu * (Q_liv+Q_pve - CL_pls / B2P * BW) * V * f_cell)

For me, this needs to be corrected as intrinsic clearance would be:
CL_int = CLspec * (E / f_cell) * V * f_cell
where E is the hypothetical enzyme concentration of 1 µmol/L (of an unknown enzyme) in mixed liver tissue. Thus, f_cell cancels out and we would obtain:

CLspec = CL_pls * BW * (Q_liv+Q_pve) / (fu * (Q_liv+Q_pve - CL_pls / B2P * BW) * V)

With this equation, your PBPK plasma clearance (output) would be approximately equal to your input plasma clearance (at least for compounds where the wll-stirred assumptions hold approximately true).

Work around: set f_cell in the building block of your molecule to 1 in the "total hepatic clearance" process.

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