Possibility to scale Albumin levels in the 'individual' building block

[Incei]

As Fu is a compound specific parameter, when creating/implementing a special population in PKSim with a reduced relative Fu e.g. due to renal failure, it is currently not possible to set this in the individual/population. We should think about a possibility to scale Albumin levels in the individuals (e.g. via alternative fu calculation), rather than having to change this in addition in the compound when selecting such a special population for simulation.

All ideas are welcome.

[JanSchlender]

Scaling would be nice. However, I would like to have a direct input for albumin. Currently the back-calculation using the volume fraction is quite cumbersome and does not allow the user to have a direct feedback of the absolute albumin level in the desired population. A direct input could then trigger the adaptation of the fu. In case the user adapts the absolute protein level in a certain population and wants to scale it to another age, gender or ethnicity, the scaling could be done applying a relative change with respect to the default value.

[msevestre]

@Incei @JanSchlender Where is the Albumin concentration used in the model? Also there is the parameter Plasma protein scale factor that I think is exactly what you need. Why cannot you use it?

[JanSchlender]

Assume a case where you have a population with a known fu and a unknown Albumin concentration. You can enter the fu directly and build your model. When you would then like to scale the model to a special population of which you know the albumin concentration and want to estimate fu, you do not now to which extent you need to spin the scaling factor (or you do the count back as described earlier).

[msevestre]

@JanSchlender Can you explain WHERE this Albumin Concentration would be used? More precisely, would it be used to override somehow the value of fu in the compound? I have trouble understanding the workflow

[JanSchlender]

Currently, the "true" fraction unbound is calculated as f_u=1/[(1-f_protein )+f_protein×K_protein ]. f_protein is the volume fraction of albumin in plasma (2,2%). It is not an input parameter and thus we apply the scaling factor. The user needs to look up the volume fraction in the manual and can then compute the concentration which can be compared to the albumin level in his population of interest. Could the volume fraction or the resulting albumin concentration be depicted in the individual?

[msevestre]

but fu is a user input. Or do you mean you would like to have a way to calculate fu on your behalf?

On Tue, May 23, 2017 at 3:22 AM Jan Schlender notifications@github.com wrote:

Currently, the "true" fraction unbound is calculated as f_u=1/[(1-f_protein )+f_protein×K_protein ]. f_protein is the volume fraction of albumin in plasma (2,2%). It is not an input parameter and thus we apply the scaling factor. The user needs to look up the volume fraction in the manual and can then compute the concentration which can be compared to the albumin level in his population of interest. Could the volume fraction or the resulting albumin concentration be depicted in the individual?

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[JanSchlender]

1. Population: fu known, Albumin concentration unknown. --> User applies fu without considering the albumin concentration
2. Population: fu unknown, Albumin concentration known. --> How should the user scale the fu?

Scaling factor and change of fu would be arbitrary. Here, the user needs to type in the albumin concentration or needs to know the default albumin concentration in order to compute the altered fu.

[msevestre]

ok. How should it look like in the app? any idea?

[TheiBa]

I guess the key is to optionally take along the binding constant (K_protein) and albumin reference concentration of a typical healthy individual and then, depending on the question at hand, use those or f_u. Conceptionally, somewhat similar to BW/BH/BMI, I guess.

E.g. inputting an f_u, K_protein can be calculated assuming a given albumin level. In a situation where you then want to translate to a situation where you know how the albumin level is altered, you can use that information along with K_protein to predict f_u changes ala McNamara https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751289/ … not only for pediatrics … but for those you want to, e.g., have the option to test an alternative (to the current implementation) “continuous” ontogeny.