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Kp scalar value #513

Closed humblewarrior closed 4 years ago

humblewarrior commented 4 years ago

Hi! I have couple of questions.

1) Where can I find Kp scalar (ratio of drug concentration in tissue and plasma) to optimize Kp values for various organs? 2) Where is the place to enter Vss value in the software? 3) What is the difference between "venous blood" and "peripheral venous blood"? I am trying to predict plasma concentration. Which one should I go for?

Regards, Sumeet

jzq90 commented 4 years ago

I think there isn't a way to adjust Kp and Vss directly in a PBPK model. These parameters are dependent on the properties of molecules and physiological parameters. The same reason you can only adjust organ permeability and solubility but can't adjust bioavailability directly. But I think you can use the real data to fit LogP, solubility and permeability in a parameter identification like below: https://github.com/Open-Systems-Pharmacology/Forum/issues/495

jzq90 commented 4 years ago

From the instruction of software: 图片

msevestre commented 4 years ago

This is the correct answer. Thanks @jzq90

humblewarrior commented 4 years ago

So, what I am trying to understand is how this software is different in terms of its functionality, specifically in terms of entering Kp values for different organs. I am trying to replicate results from previous study, and I have Kp values of all the organs from that study. I just don't see where I can enter those Kp values, to get similar tissue-concentration time profiles. I see that we can enter partition coefficient in parameters ->Distribution -> Partition Coefficient, and there are two types of partition coefficient: 1) Interstitial:plasma and 2) Intracellular Plasma.

StephanSchaller commented 4 years ago

is different in terms of its functionality

What do you mean here? Different to what, and what study are you trying to replicate?

There is also the calculated value for Kp blood/plasma in parameters ->Distribution -> Partition Coefficient given: image

as @jzq90 correctly stated, the Kp is csalculated from your lipophilicity and such. So in a way you have to adjust the input values (also the partitioning calculation method has an influence) to get the measured Kp.

humblewarrior commented 4 years ago

@StephanSchaller

So, the work that I am trying to replicate is in the process of getting published. In that study, the authors used Simcyp software. They have Kp value of 0.266 (which was adjusted) and then they reported Kp values of the drug in each organ. I am trying to get that. I am trying to get Kp values of the drug in each organ. How should I get Kp value of drug in each organ? Or maybe there is a way to adjust the Kp value of the drug in each organ so that my simulated, lets say brain tissue concentration is similar to the previous study?? I don't know. That is what I want so that I can compare my results with the results of that study.

I am sorry. I am still naive when it comes to PBPK and this software. I am trying to figure it out as much.

StephanSchaller commented 4 years ago

Well, be aware that SimCyp and PK.Sim differ in some of the details of how the PBPK model is built.

In any case, find out what partition coefficient calculation method they used (likely "Method 1" which should correspond to Rodgers and Rowland). So select Rodgers and Rowland in PK-Sim when you create your Simulation. You can also "by force" change the B:P partitioning in PK-Sim by changing the partition coefficient i showed above. This parameter is the same for all organs, as "blood/plasma" is organ-independent.

You can change tissue partitioning with the other Kp vlaues 1) Interstitial:plasma and 2) Intracellular:plasma.

But again, this is "forcing" partitioning by hand, and not recommended. Better find out what might be different for your compound that the predicted values don't work (tissue / cellular binding partner?).

humblewarrior commented 4 years ago

Method was by Poulin and Theil and corrected by Berezhkovskiy. I can see those methods in the software. I think you answered my question for now. Thank you so much! I really appreciate it. Stay safe!

leeking-55 commented 4 years ago

Method was by Poulin and Theil and corrected by Berezhkovskiy. I can see those methods in the software. I think you answered my question for now. Thank you so much! I really appreciate it. Stay safe!

Excuse me, did you solve your problem? If it is not recommended to modify the tissue partitioning with the other Kp vlaues 1) Interstitial:plasma and 2) Intracellular:plasma, then it is better to modify what parameters to get the KP value reported in the literature, and look forward to your reply. have a good day leeking.