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Pheonix Simulation Question


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#1 Jiexin Deng

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Posted 25 July 2013 - 05:02 PM

I have built a PBPK model using some rat biodistribution data for my drug. This is not a population dataset, and only the mean concentrations are used at each time point. I have then tried to scale the rat PBPK model to predict human plasma concentrations by using human physiological parameters. In my model I do not have any ETA's because I only used the mean concentrations for my model, but I did specify two sigma's with proportional error model. My question is this: does the Pheonix simulation mode take the residual error model into account or it only uses the fixed effect parameters estimated with rat data? Does the simulation outputs Cb or CbObs?

 

 

I have another question unrelated to this. I read that Pheonix can perform Monte Carlo Simulations under the population mode. I know that the fixed effect parameters estimated with the base model are used for the simulation. Does the Monte Carlo simulation randomly sample a normal distribution of those fixed effect parameters estimated previously (from the 95% confidence interval) and use those sampling parameters for its simulation replicates for each individual? What if we have some parameter estimates with a confidence interval from previously studies and would like to use those parameter distribution for the Monte Carlo Simulation. Is there a way to specify this in Pheonix?

 

Thank you so much.



#2 serge guzy

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Posted 25 July 2013 - 07:02 PM

Dear colleague If you do not have etas at all, then I guess you used the simulation versus simple option when unclicking population. As far as I know this will give you only the predicted responses and not the the response + noise. If you want to get the noise too added to your response (CObs versus C), then just add a random effect and out a very small variance. In the population mode, you will get both the predicted response © without noise and what could be an observation CObs which includes the noise. If you are still in trouble, let me know and I will send you a demo example. When you shift to the population mode, you model parameter is now defined in terms of both fixed and random effect. For example stparm(Cl=tvCl*exp(nCl)) ranef(diag(nCl)=c(0.1)) tvCl is the fixed effect which is what you used when you did not have any random effect. Now, nCl is a sample from a normal distribution with mean 0 and variance you defined just below in the statement ranef. ranef stands for random effect, diag means no covariance, c means vector and then you put the variance, here 0.1. The program will always simulate from a normal distribution with mean 0 and variance defined in the ranef statement. However Cl is equal to tvCl*exp(simulated random effect) and therefore you will get what we call a lognormal distribution for Cl. The median of that distribution is tvCl. If you want a pure normal distribution for cl, you can change the option by clicking on parameter/structural and look under style where you can select different options for distribution (default is lognormal). Suppose you define sum + eta. This stands for normal distribution for your parameter. The mathematical formula is stparm(Cl=tvCl+nCl) same meaning for nCl but since you add tvCl to it, the result will be a normal distribution for Cl Every time you shift to another individual, the program selects a new random sample (nCl) You are talking about uncertainty here and not population variability, These are two completely different things. However there is a way to quantify the impact of the uncertainty in your fixed effect and reflect it through simulation. The problem is often the confidence intervals are asymmetrical and therefore it is more difficult to define the uncertainty distribution. You can make an assumption that the standard error give to you can be used to simulate a normal distribution with mean at the estimate and variance equal to the square of your given standard error. This is risky because you can get negative values for your parameter. If you have the standard error of your parameter in the log domain, then you can take the log of your estimate and use that standard error as the standard deviation for your simulation, then you exponentiate the result to get the values of your model parameters that now will never be negative. I hope it helped. best Serge

#3 Jiexin Deng

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Posted 25 July 2013 - 09:41 PM

Thank you so much for your reply. I did try your suggestions out. However, I am not familiar with using population mode. Could you please send me the demo file to make sure I am doing this right?



#4 serge guzy

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Posted 25 July 2013 - 10:35 PM

Dear colleagues
THE PROJEcT DEMO FOR POP SIMULATION IS ATTACHED. I DID A MODEL WITH VARIANCE OF 0.1 (~30% CV) AND THEN ONE WITH VERY SMALL VARIANCES. FOR VERY SMALL VARIANCES, YOU SHOULD GET C AND E VERY SIMILAR ACROSS THE DIFFERENT PATIENTS (EMULATE FIXED EFFECT SIMULATION ONLY). CObs and EObs contain the noise of about 10% cv for both responses.
BEST
SERGE [file name=pop_example_simulation.phxproj size=1418366]http://pharsight.com/extranet/media/kunena/attachments/legacy/files/pop_example_simulation.phxproj[/file]

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Edited by Simon Davis, 08 May 2018 - 05:43 PM.
Edited to enable download.


#5 shekhar.udct@gmail.com

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Posted 08 May 2018 - 06:33 AM

Can you please share the phoenix project file. 

 

Dear colleagues THE PROJET DEMO FOR POP SIMULATION IS ATATCHED. I DID A MODEL WITH VARIANCE OF 0.1 (~30% CV) AND THEN ONE WITH VERY SMALL VARIANCES. FOR VERY SMALL VARIANCES, YOU SHOULD GET C AND E VERY SIMILAR ACROSS THE DIFFERENT PATIENTS (EMULATE FIXED EFFECT SIMULATION ONLY). CObs and EObs contain the noise of about 10% cv for both responses. BEST SERGE [file name=pop_example_simulation.phxproj size=1418366]http://pharsight.com/extranet/media/kunena/attachments/legacy/files/pop_example_simulation.phxproj[/file]



#6 Simon Davis

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Posted 08 May 2018 - 05:51 PM

Shekhar, some of the older threads were migrated from an older platform and sometimes I need to manually edit them to enable downloading, I have done that for the above post.

 

If you find any other posts with broken links please use the 'report post' feature and I will try to fix those too.

 

 Simon.






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