4 replies to this topic

[vetpharma]

Hi, 

 

I modeling a compound using pop PK which follows a non linear absorption. For dose dependent Ka, could you please confirm if the following syntax is correct? 

 

test(){

covariate(Dose)

deriv(Aa = - Ka * Aa)

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

dosepoint(Aa)

nlKa = tvKa * (1-Dose/(Dose+D50))

C = A1 / V

error(CEps = 0.1)

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

stparm(D50 = tvD50 * exp(nD50))

stparm(Ka = tvKa * exp(nKa))

stparm(V = tvV * exp(nV))

stparm(Cl = tvCl * exp(nCl))

fixef(tvKa = c(, 1, ))

fixef(tvV = c(, 1, ))

fixef(tvCl = c(, 1, ))

fixef(tvD50 = c(,1,))

ranef(diag(nV, nCl, nKa, nD50) = c(1, 1, 1, 1))

 

The model is not working so I would appreciate it if you help me to troubleshoot the problem. 

Is that correct to introduce D50 as a param? 

Is that correct to map Dose in Aa and also as covariate or I should separate them?

 

Regards

Amir

[bwendt@certara.com]

Hi Amir,

 

if you are interested in modeling nonlinear absorption, I would kindly refer you to exercise PK42 from the Gabrielsson book: "Pharmacokinetic and Pharmacodynamic Data Analysis - Concepts and Applications, 5th Edition, by Gabrielsson Johan and Daniel Weiner"

 

His implementation uses a different approach, e.g. saturating the amount of compound in the absorption compartment:

 

deriv(Aa = - Vm * Aa / (Km + Aa))

 

You could define Vm and Km as population parameters, e.g. with random effects included.

 

I would suggest you apply this approach first and see whether it helps to represent your data.

 

Bernd

[dlweiner]

Amir,

 

As Bernd suggested, the G&B book has use of an MM model for this (PK42).

 

The parameterization you are using (1-Dose/(Dose+D50)) is more often used for modeling bioavailability (F).  There are a few problems with your attempt at using this for Ka.  The nonlinear function needs to be a structural parameter, not an eta (n).  The function you are using is unitless, but Ka has units 1/time.  Lastly, you are using 1's (the default) for initial estimates, and that is often a problem.

 

Dan

[vetpharma]

Hi Bernd and Dan,

 

Thanks for your recommendations, I will certainly try that. However, I have a problem with the model running. 

 

The problem is same as when I try to define transit compartment in the model (below). 

The model starts running but after the first iteration for a few seconds it turns back with terrible fitting. I am a bit in doubt in the model building for nonlinear Ka, so I asked you, but the same trend happened for transit compartment and delay function. Do you think that there is a problem or it is normal?

 

 

Transit(){

#deriv(Aa = - Ka * Aa)

transit(Aa, mtt, ntr, max=50, out=-Ka * Aa)

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

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

C = A1 / V

error(CEps = 0.875127242290243)

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

stparm(Ka = tvKa * exp(nKa))

stparm(V = tvV * exp(nV))

stparm(Cl = tvCl * exp(nCl))

stparm(mtt = tvmtt)

stparm(ntr = tvntr)

fixef(tvKa = c(, 0.728509724154436, ))

fixef(tvV = c(, 0.0237209174816188, ))

fixef(tvCl = c(, 0.0176748737356305, ))

fixef(tvmtt = c(,2,))

fixef(tvntr = c(,2,))

ranef(diag(nV, nCl, nKa,) = c(0.36942176, 0.10711289, 0.47215645))

}

 

 

Amir

[bwendt@certara.com]

Hi Amir,

 

we can only diagnose fitting problems with a Phoenix project file. If you can't share publicly you may want to send it to support@certara.com

 

Bernd