minimal PBPK in PML with IV PO dosing why is F calculated for IV?

Phoenix Certara Forums PML School
1

I have built a minimal PBPK model based on that of Fiserova-Bergerova V. Inhalation Anesthesia using physiologically based pharmacokinetic models. Drug Metab Rev. 1992;24:531-557

The project is attached. My question, why is Phoenix reporting F for the IV dosed subjects? How do I get the software to recognize IV F = 1?

PS this data is not for sharing.

thc for certara.phxproj (1010 KB)

2

William, there are likely multiple ways to do this, but I suggest you modify the Aa dosepoint statement as follows…

dosepoint(Aa, idosevar = AaDose, infdosevar = AaInfDose, infratevar = AaInfRate, bioavail=F)

then remove “F*” from the DEs for Aa and Agut, as dosepoint will then automatically adjust for F for oral dosing.

deriv(Aa = - (Aa * Ka))
deriv(Agut = (Qgut * C1)- (QHPV * Cgut) + (Aa * Ka))

Hope that helps,
Dan

3

Yes thank-you for the prompt reply.

4

Dan

I made the changes you suggested, but I am still getting F reported for the intravenous subjects. The project is attached again.

thc for certara.phxproj (1010 KB)

5

William,

Since F is a structural parameter, NLME will try to find a population estimate and calculate a posthoc value for each subject irrespective of dose route.
Note that the F values in posthoc-table for the subjects with IV are shrunk to the structural parameter value with zeroed eta: ilogit( tvFexp(nF) = ilogit( 0.917678exp(0)) = 0.714569
NLME failed to find nF for those subjects since it is impossible.
The attached project file shows you a method to distinguish the subjects by their respective dose routes. It defines a covariate ‘PODoseFlag’ and applies it to the definition of parameter F.

Bernd

[attachment=3336:thc for certara.phxproj]
thc for certara.phxproj (2.06 MB)

6

Bernd: As you probably noticed, I used up a lot of covariates in this model. How else can I get PML Phoenix to use weight and cardiac output of the individuals to multiply with a scalar (ie %CO * patients CO) for a specific tissue without using covariates?

Bill

7

Bill, I do not see any issues to work with multiple covariates. The way you are using covariates in your model looks fine to me.

8

Bernd; You don’t see a problem in this reduced version of the model, but when I add the 2 metabolites I triple the number of covariates and I think I run into the 32 covariate maximum, because PML seems to ignore the last added covariates. How is that 32 max counted? I think it is for every call on a covariate, ie for Vc1, Vc2 and Vc3 the wieght covar is called 3 times. It is easy to reach 32 when you add all of the tissue and flow parameters *3!

Bill

Can the covariate max be expanded?

9

Bill,

there is no maximum of 32 covariates. There might have been in a previous version of Phoenix, but the current version, 8.1., does not have a maximum there. The only restriction that we found for covariates is *Maximum number of covariate categories or occasions = 40.

Please check the project file attached where we created a hypothetical examples in PHX8.1 with 45 covariates included in a single parameter, and found that PML correctly incorporates all the covariates inside. In addition, it runs without any issue, but extremely slow:

SingleParamInvolving45Covariates.phxproj (1.29 MB)

Please note that there is a similar topic that was posted in 2013:

https://support.certara.com/forums/topic/482-too-many-covariates-in-population-model/.

It seems that, at that time, it has this maximum 32 restriction. To avoid this, Serge proposed using Scenario run mode to reduce the number of covariates, and then do a covariate search (see details inside this link).

Hope, this helps,

Bernd