Failed to obtain PK parameter CV percents

Phoenix Certara Forums Modelling and Simulation
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Hello,

Can anyone help explain why would I fail to obtain PK parameter CV percents and omega standard error by solely changing the residual variability methods (CEps) from additive to multiplicative or combined?

Everything else seemed normal.

Thanks!!

2

Hello,

The standard errors are calculated as a second step after fitting the model. Standard errors for the parameters are computed using the Hessian matrix. Changing the model residual error model will change the hessian matrix because you have different parameters (sigma is a parameter to be estimated) and in some cases the Hessian cannot be resolved. Try going to the run options tab and changing the error estimation method to another method (e.g., Sandwich or Fisher). It should not affect your fit.

Ana

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Thanks for your help, Ana. Changing the error estimation method could not fix the problem. Had to reduce the number of parameter estimations..

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Sinyinlim - did you try restarting your model using the final estimates from the previous run; quite often that helps me get CV% calculated sucessfully. Swapping to QRPEM may also help - but sometimes with more complicated models you still won’t get them unfortunately as you’ve seen.

Simon.

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Hi Simon,

I tried swapping to QRPEM, it did calculate the CV% successfully, but like you said, not always. Thanks for the helpful comment!!

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Hello,

I am facing similar issues - such that no CV% are obtained in FOCE-ELS method, but they are obtained in QPREM.

I even used the estimates obtained from QPREM as my initial estimates for parameters while applying the FOCE-ELS and tried changing the method as well - Sandwich vs. Hessian vs. Fisher

Can you please share insights into what could be the issue?

Is there a particular error model that does not seem to work for FOCE ELS?

Can you please share some experiences and solutions?

Many Thanks,

Charvi

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Hi Charvi,

as Ana noted in her first reply, standard errors are computed using the Hessian matrix and this computation might fail. This is common in any regression software when you need to invert a matrix. The hessian might not be obtainable and then you cannot compute standard error. More often than not the model is overparametrized/unstable.
You can also try to change the error estimation method on the Run Options tab by using forward rather than central where forward is faster but less precise than central. Apart from that you typically start with hessian, then move to sandwich and last try fisher. If none of this works, then use the Bootstrap method.

Bernd

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Hi Bernd,

Thank you for your response, this helps.

Regards.

Charvi

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Hi All.

On a related note - as I understand QPREM does not consider bounds on fixed effects. In cases where bounds are necessary for certain parameters such as bioavailability, fraction etc. - is it not recommended to use it? Or is there any other way a fixed effect can be constrained while using QPREM?

Thanks,
Charvi

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Hi Charvi,

you can use the ilogit transform to constrain anything between 0 and 1. Here is the PML to constrain bioavailability, F:

dosepoint(Aa, bioavail=F)

F=ilogit(Flogit)

stparm(Flogit=tvFlogit * exp(nFlogit))

fixef(tvFlogit = c(,0,))

ranef(diag(nFlogit)=c(0.1))

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Thanks Bernd for your response.

This helps.

Regards,

Charvi

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