IOV on F

Phoenix Certara Forums Modelling and Simulation
1

Hi,

I was having an interesting conversation today with some Pharsight consultants and they mentioned that you can perform IOV modeling on F for model parameters which are assumed to be a fraction of the bioavailability term i.e. CL/F V/F etc. Can anyone explain how this looks in the PML code as the problem is not obvious to me.

Thanks!

Lance

2

Dear Lance

I made a project for you. IOV on F only to make sure we see the effect of IOV on the PK.

The only trick is to define occasion change just before the next dose because fcovariate does not set up the new value at the dosing time (bug fixed I think in 15) and backward covariate is not appropriate here(especially in simulation mode).

please take a look and let me know if all is clear.

best

Serge

f_iov.phxproj (1.37 MB)

3

Hi Lance additional info :

To be able to add bioavail you need to be in graphical or textual model:

In Graphical mode:

Click on absorption compartment Aa.

Click the bioavail check box chose a name for the F parameter e.g. FREL

Insert a parameter and name it FREL

Choose to add the OCC variable as a covariate and define it as an occasion variable

Of course if you are familiar with textual mode you can just go to the model text and edit as you like:

test(){

deriv(A1 = - (Cl * C) + (Aa * Ka))

deriv(Aa = - (Aa * Ka))

C = A1 / V

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

error(CEps = 1)

observe(CObs = C + CEps)

stparm(V = tvV * exp(nV))

stparm(Cl = tvCl * exp(nCl))

stparm(Ka = tvKa * exp(nKa))

stparm(FREL = tvFREL * exp(nFREL + nFRELx0*(OCC==0) + nFRELx1*(OCC==1) + nFRELx2*(OCC==2)))

fcovariate(OCC)

fixef(tvV = c(, 1, ))

fixef(tvCl = c(, 1, ))

fixef(tvKa = c(, 1, ))

fixef(tvFREL = c(, 1, ))

ranef(diag(nV, nCl, nKa, nFREL) = c(1, 1, 1, 1))

ranef(diag(nFRELx0) = c(1), same(nFRELx1), same(nFRELx2))

}

Note how all the occasion random effect have the same variance as show on the last line

Also

FREL = tvFREL * exp(nFREL + nFRELx0*(OCC==0) + nFRELx1*(OCC==1) + nFRELx2*(OCC==2)))

Does not ensure that your F is between 0-1 ( this is fine if we are in relative F if you are modeling absolute F versus IV you might want to : use an ilogit of the expression:

stparm(FREL = ilogit(tvFREL + nFREL + nFRELx0*(OCC==0) + nFRELx1*(OCC==1) + nFRELx2*(OCC==2)))

And as Serge pointed out you data need to be built correctly for the software to understand well the transition between the occasions.

The bug that has been fixed is that the software set up the covariate value after the obsercation

ID Time Cobs OCC

1 0 . 1

1 12 1 .2 1

1 24 2.1 2
with fcovariate the occasion value 1 from time 12 to time 24 since we have a Cobs=2.1 at 24 it is still applying the OCC=1 at this obs and then it switches occasion to 2.

if you want obs 2.1 to be treated as occ 2 you have to set the covariate to 2 before the observation

ID Time Cobs OCC

1 0 . 1

1 12 1 .2 1

1 24 2

1 24 2.1 2