Dose a biomarker and use its PK as the Effect which is modified by a co-dosed drug

Phoenix Certara Forums Modelling and Simulation
1

Hi, i’m looking for suggestions on how i can use the graphic model builder in Phoenix to build a PK/PD Emax model where both the drug and biomarker (Effect) are dosed together. Without going into too much detail, I am assessing drug activity in mice where animals receive a single oral dose of drug to block the target, and then one hour later the mice are challenged with a single oral dose of an endogenous biomarker. The inhibiting drug thus increases the exposure to the biomarker and decreases the formation of biomarker metabolites. So i’m looking for a way for the biomarker to have its own PK and simultaneously be the Effect, because the biomarker will have its own PK profile in the absence of drug.

The reason for this is because it allows me to test drug activity in wild-type animals which have very low concentrations of the biomarkers of interest. Much higher biomarker concentrations are expected in the disease state.

thank you

Chuck Locuson

2

Hi Chuck,

I cannot think of an easy way to build such a model via the Graphical tool. You would need to use a turnover model to define the endogenous building of the biomarker. But you would also need an absorption compartment for the biomarker that is dosed orally. On top of that you want to stimulate formation of the biomarker by the drug. This combination can only be modeled in textual mode.

Here is a first attempt:

test(){
dosepoint(Aabiom)
deriv(Aabiom = - (Aabiom * Kabiom))
deriv(Abiom_end = Kin - Kdeg * Abiom_end)

sequence{Abiom_end = (Kin) / (Kdeg)}
deriv(Abiom = Abiom_end - (Cl * Cbiom) + (Aabiom * Kabiom))
Cbiom = Abiom / Vbiom

dosepoint(Aadrug)
deriv(Aadrug = - (Aadrug * Kadrug))
deriv(A2 = (Aadrug * Kadrug)- (CLdrug * Cdrug))
Cdrug = A2 / Vdrug

stparm(Kabiom = tvKabiom * exp(nKabiom))
stparm(Vbiom = tvVbiom * exp(nVbiom))
stparm(Cl = tvCl * exp(nCl))
stparm(Vdrug = tvVdrug * exp(nVdrug))
stparm(Kadrug = tvKadrug * exp(nKadrug))
stparm(CLdrug = tvCLdrug * exp(nCLdrug))
Kin = Kin0 + Emax*Cdrug/(E0 + Cdrug)
stparm(Kin0 = tvKin0 * exp(nKin0))
stparm(Kdeg = tvKdeg * exp(nKdeg))
fixef(tvVbiom = c(, 1, ))
fixef(tvCl = c(, 1, ))
fixef(tvVdrug = c(, 1, ))
fixef(tvKadrug = c(, 1, ))
fixef(tvCLdrug = c(, 1, ))
fixef(tvKabiom = c(, 1, ))
fixef(Emax = c(, 1, ))
fixef(E0 = c(, 1, ))
fixef(tvKin0 = c(, 1, ))
fixef(tvKdeg = c(, 1, ))
ranef(diag(nVbiom, nVdrug, nKadrug, nKabiom, nCLdrug, nKin0, nKdeg, nCl) = c(1, 1, 1, 1, 1, 1, 1, 1))
}

Let me know if this works.

Bernd

model.png
model.png696×475 4.03 KB

3

Dear Bernd, wanted to thank you very much for the assistance

Cheers

Chuck