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Finf and Frel


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#1 ARINDAM PAL

ARINDAM PAL

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Posted 22 July 2013 - 03:35 PM

Dear Sir/Ma'am

 

I have few questions on IVIVC, I would be grateful if you can answer these:

 

1) when should we keep Finf "fixed" or "estimated" ?

2) Can we keep Finf < 1 and if that is so, what is the rationale ?

3) I have found in an ivivc exercise that, %cumulative disso. release (at 0.25, 0.5, 1 & 2 hr) is lesser for a formulation compared to others, the Frel (fraction dissolved in vitro) for that formulation is however greater compared to ohers. The prediction of PK (Cmax & AUC values) came out to be greater also for that formulation compared to others. Does that mean % cumul release have no bearing on AUC or Cmax and it all depends on Frel for ivivc prediction ?

 

Thanks

Arindam



#2 Simon Davis

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Posted 23 July 2013 - 10:50 AM

Arindam,

 

 there definitely advantages in keeping Finf "fixed" as it reduces the complexity of the model since there is one less parameter to be estimated. Typically I would fix at 1 since I would expect Fraction dissolved at infinity to be 1 (ie.complete dissolution)

 

to fix Finf < 1 I guess your rationale would be that you are NOT seeing complete dissoultion; perhaps you removed the dosing mechanism e.g. a transdermal patch after a certain time point and know that in that period only 60% has been released ?

 

for 3) I think it would be helpful if you posted the project as I try and visualise what you are describing.

 

but it is possible that a formulation could be SLOWER dissolving at early timepoints but overall release more in the experiment's timeframe.

 

 Simon.



#3 ARINDAM PAL

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Posted 23 July 2013 - 12:47 PM

Dear Simon

Thank you very much for the prompt response.

 

I am attaching the excel sheet of disso. profiles (prediction batches). A look into the plots says it all what I meant - plot of time vs. % cumul rel indicates T1 to be slower in almost all time points and the overall release is low compared to T2. However, going by the plot of time vs. Frel, T2 seems to be a bit faster and releasing more drug than T1.

 

Obviously, when my ivivic model is based on Frel or "Fdiss", T1 is having higher predicted Cmax & AUC than T2, even though the drug release at all time points and overall is lower for T1.

 

This strikes an ambiguity, as exposure (AUC) is highly dependent on overall drug release, and even when the release is slower and lower, the Cmax & AUC is higher for T1.

 

I would be grateful if you also find time to kindly answer my question on Tcut-off, I posted on 19 Jul'13.

 

Regards

Arindam






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