modeling flipflop PK in WinNOnlin

Phoenix Certara Forums Modelling and Simulation
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Hi Pharsight Expert: I have a data set from IV and SC dosing at the same dose. The terminal half life is much short in IV compared to SC. I suspect a flipflop PK. My question, can WinNonlin model flipflop PK? Any input is highly appreciated! Thanks, Ali

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Yes WinNonlin can model flip-flop kinetics. As you correctly state, the term “flip-flop” simply means that the absorption rate constant is slower than the elimination rate constant. Depending on your dataset, you can either model the IV and SC data together using a common k for the elimination rate constant. Or you can model the IV data alone and use the estimate of the elimination rate constant in the SC model. An alternate way to model the data would be to use Ka, CL, and V. Then you don’t have to worry about modeling the elimination rate constant. Good luck! Nathan

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Hi Nathan:

Thank you for the response. I do not know how to model iv and sc data together. I tried model iv data alone first. But I do not know how to use the elimination rate constant from iv to the sc model. I attached a data set and phoenix proj here for your reference. Can you please show me how to model iv and sc data together and how to use the kel from iv to sc?

Your kind help is highly appreciated!

Sincerely,

Aiqun [file name=Plasma_IV__SC.phxproj size=461319]Certara | Drug Development Solutions (451 KB)

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Dear Aiqun
I am attaching a demo project that shows you how to model both IV and SC together(you need to use the graphical feature and add an IV dose when taking as template extravascular input). Let me know what is not clear.
Here in your example, the problem seems that all the PK parameters may be different across the 2 routes. If that is the case, you cannot fit both together assuming same model parameters.
What I did is to give you data where the model parameters are the same across the 2 routes except that I added bioavailability for SC route.

I also used the reset tab to washout all the influence of the IV data when I gave the SC. The assumption is that these are 2 separate sets of observation but with common PK.
When you do that and uncheck the sort button, you can also reset the time to zero when you give the SC dose.
Look at it and you can see that in this example Ka is smaller than ke and the fit is for both sets together.
Let me know if you need further help.
Best
Serge [file name=Plasma_PK_IVSC_serge.phxproj size=371015]Certara | Drug Development Solutions (362 KB)

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Hi Serge: I have a similar question about modeling IV and SC together, with SC showing flip-flop kinetics. Can you please share the demo project? I could not locate the demo project from your link above.

Another question: Can I model SC data alone with flip-flop kinetics (without iv PK data) to get ka?

Thanks very much!

Chun Li

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Hi Serge: I have a similar question about modeling IV and SC together, with SC showing flip-flop kinetics. Can you please share the demo project? I could not locate the demo project from your link above.

Another question: Can I model SC data alone with flip-flop kinetics (without iv PK data) to get ka?

Thanks very much!

Chun Li

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Hi Chun Li, both the above attachments should now be downloadable - if not please report the message and I will look at it again,

Simon.

Chun, I am using Firefox as my browser and I simply mouse over the link and can then click on it and it downloads straight away.

Simon.

download.jpg
download.jpg1069×466 123 KB

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Hi Simon:

Thanks for the quick reply. How do I download the attachments? When I tried to type the following link in our internet browser, it returned an error saying “sorry, we couldn’t find that”.

Thanks,
Chun

http://www.pharsight.com/extranet/media/kunena/attachments/legacy/files/Plasma_PK_IVSC_serge.phxproj