PML for absorption model with 2 first order absorption rate

Phoenix Certara Forums PML School
1

Hi, I am working on a population Pk model focusing on the absorption phase of an oral drug. I found this study with an interesting absorption scenario (please see figure):
After oral administration, the drug goes to an absorption compartment with two depots (depots 1 and 2). Then the drug moves from depot 1 to 2 with Ka1 and Tlag and finally from depot2 to the central compartment with Ka2. So based on this scenario, we have two first-order absorption rates. My question can I get help on how to write PML lines that describe this process.
I am also attaching the article for your reference.
pharmaceutics-12-00374-v234125.pdf (2.08 MB)

figure.jpg
figure.jpg1200×1060 81.1 KB

2

Hi David,

Thanks for sharing the publication. I have attached the project file (simulation) based on the estimates from this paper using a graphical model

Model.jpg
Model.jpg423×486 18.9 KB

The PML code for this model is:

test(){
deriv(A1 = - (Cl * C) + (A2 * Ka2))
urinecpt(A0 = (Cl * C))
deriv(Aa = - (Aa * Ka1))
deriv(A2 = (Aa * Ka1)- (A2 * Ka2))
C = A1 / V
dosepoint(Aa, tlag = (Tlag), idosevar = AaDose, infdosevar = AaInfDose, infratevar = AaInfRate)
error(CEps = 0.357)
observe(CObs = C * exp(CEps))
stparm(V = tvV * (1+(TotalProtein-7.6)*dVdTotalProtein) * exp(nV))
stparm(Cl = tvCl * (1+(TotalProtein-7.6)*dCldTotalProtein) * exp(nCl))
stparm(Tlag = tvTlag * exp(nTlag))
stparm(Ka1 = tvKa1 * exp(nKa1))
stparm(Ka2 = tvKa2 * exp(nKa2))
fcovariate(TotalProtein)
fixef(tvV = c(, 1717060.491, ))
fixef(tvCl = c(, 447163.154, ))
fixef(tvTlag = c(, 0.196, ))
fixef(tvKa1 = c(, 3.187, ))
fixef(tvKa2 = c(, 3.183, ))
fixef(dVdTotalProtein(enable=c(0)) = c(, -1.049, ))
fixef(dCldTotalProtein(enable=c(1)) = c(, -0.804, ))
ranef(diag(nV, nCl, nTlag, nKa2, nKa1) = c(0.326, 0.16, 0.107, 0.557, 0.556))
}

Simulation-based on this model

[attachment=3679:plots.jpg]

Please let me know if you need further assistance. Thanks and regards

Mouli
Simulation01.phxproj (376 KB)

plots.jpg
plots.jpg389×371 28.9 KB

3

Thank you Mouli for your time providing me a clear explanation on how to do this scenario using PML.

I have another question, I have been working on different absorption scenarios recently and I came up with this model :

cfMicro(A1, Cl / V, Cl2 / V, Cl2 / V2, first = (Aa = Ka))
dosepoint(Aa, tlag = Tlag,duration = TK0 )
C = A1 / V

The fit I got was a very good one but at that time I was thinking how to describe it. After reading the above article I came up with this possible explanation for this scenario:

After dosing the drug moves from depot 1 to 2 by zero order absorption rate (TK0) and Tlag and then from depot 2 to central compartment by first order absorption (Ka).

I am not sure if this explanation is quite accurate ?

Thanks