Modeling short-term infusion (C after IV infusion stop) - sequence statement

Phoenix Certara Forums Modelling and Simulation
1

Hi,

I am trying to simultaneously model PK/PD data from drug input that is similar to short-term infusion with the new Phoenix PML language but keep getting error (no error message but %CV was not calculated for parameter estimate and the shape of the curve is totally off).

When I use WNL ASCII, this code works for me.

T=X
tau = 24
IF T <= tau THEN
ti = T
ELSE
ti = tau
ENDIF

Ceff = Css*(1-exp(-Ke*ti))exp(-Ke(T-ti))

d(z1) = Kin * (1 - Emax * Ceff/ (Ceff + EC50)) - Kout * z(1)

However because I have data from several doses, the new Phoenix model would be more convenient. So similarly, I tried this code (which didn’t work):

double(ti)
Ceff = Css*(1-exp(-Ke*ti))exp(-Ke(t-ti))
dosepoint(Ceff, idosevar = Css)
Tau=24
sequence{
ti=t;
sleep(Tau);
ti=Tau;
}

deriv(E = Kin * (1 - Emax * Ceff/ (Ceff + EC50)) - Kout * E)

sequence{E = 100}

error(EEps = 0.1)
observe(EObs = E + EEps)

There was no error message but %CV was not calculated for parameter estimates and the shape of the estimated profile was totally wrong, i.e. flat at 100% (baseline) for the first 24 h (Tau) before drug effect starting after Tau.

I suspected that the problem was with the sequence statement. What would be the correct way to model this IF statement with Phoenix modeling?

Thank you!

Pam

2

could you post your project? or at least a representative set of data as that may make it easier to guide your model development. thanks, Simon.

3

Hi Simon.

Example data set is attached. The data is for in vitro treatment, where cells were treated for 24 h before drug were removed and cells were allowed to recover for up to 48 hours. We know that this drug uptake is slow (large molecule) and it degrade over the incubation period as well. Because of these reasons, we thought that short-term infusion model will work well to characterize intracellular PK of this drug but other suggestions are very welcome.

Thanks!

Pam

102617.xlsx (8.47 KB)

4

Hi Pam,

At a glance, one thing I noticed with your code is that you have upper case Ke and also lower case ke. PML is case sensitive.

Ana

5

Hi Ana,

That was actually my typo when I renamed the parameter to post here. The actual code are not mismatched. I edited the code, so they are now matching.

Thanks!

6

The provided information is incomplete. Can you please provide a full project where you have the winnonlin model workign and what your tried in PML ?

I am not sure if we need the sequence in your case has pml dosepoint knows how to handle infusions with fixed duration and or modeled durations.
Bests,
Samer