How to code different dose levels on different occasions in the same individual

Phoenix Certara Forums Modelling and Simulation
1

Hi everyone.

I have a data set including concentration-time data following four days repeated oral dosing of a compound in dog. Each dog (five all together) were first receiving a low dose (once a day during four days), followed by a two weeks washout period, and then again administrated with a higher dose (four days repeated dosing). Dogs were sampled after each dose level.

Please, is there anyone who can help me how to code different dose levels at different occasions but in the same dog(s) in Phoenix WinNonlin (NLME)?

I use a 1-compartmental PK model.

test(){
deriv(Aa = - Ka * Aa)
deriv(A1 = Ka * Aa - Cl * C)

dosepoint(Aa)

C = A1 / V

error(CEps = 0.2)
observe(CObs = C * (1 + CEps))

stparm(Ka = tvKa * exp(nKa))
stparm(V = tvV * exp(nV))
stparm(Cl = tvCl * exp(nCl))

fixef(tvKa = c(, 0.5, ))
fixef(tvV = c(, 35, ))
fixef(tvCl = c(, 1, ))

ranef(diag(nV, nCl, nKa) = c(0.2, 0.2, 0.2))

deriv(AUC = C)

secondary(Thalf = (0.693 * tvV) / tvCl)
}

Thanks in advance!
Therese Ericsson

2

Dear Terese

I made a project for you that demonstrates what you are looking for.

Things to remember

1: you need to uncheck the sort button in run options.

2 in input option you must select the reset button from 4 to 4. In the data set , reset column is set to 4 when you want full washout of the drug amounts in all compartments

  1. I assumed we have inter-occasion variability in clearance

I fit 100 patients with 2 occasions (low and high dose), each occasion 4 doses every day.

Similar to what you are looking for.

Let me know if you need frther help.

The project is in 1.4. This is important to shift to the 1.4 as 1.3 is way out of date.

The code is

test(){
deriv(Aa = - Ka * Aa)
deriv(A1 = Ka * Aa - Cl * C)
dosepoint(Aa)
C = A1 / V
error(CEps = 0.1)
observe(CObs = C * (1 + CEps))
stparm(Ka = tvKa * exp(nKa))
stparm(V = tvV * exp(nV))
stparm(Cl = tvCl * exp(nCl + nClx1*(occasion==1) + nClx2*(occasion==2)))
fcovariate(occasion)
fixef(tvKa = c(, 1, ))
fixef(tvV = c(, 50, ))
fixef(tvCl = c(, 20, ))
ranef(diag(nV, nCl, nKa) = c(0.1, 0.1, 0.1))
ranef(diag(nClx1) = c(0.01), same(nClx2))
}

3

The data set is attached too

4

oups, now the project should be atttached

therese.phxproj (2.19 MB)

5

Dear Serge.

Thank you so much for your reply and help. I have implemented your suggestion in my model and it works.

Thanks again.

Regards,

Therese

6

Any time.

best Regards

Serge