Dear all,
I have developed a parent and metabolites PK model.
My model building strategy is a stepwise approach.
In the first step, I just have developed parent PK model.
The absorption of the parent drug is modeled using mixed absorption model (first and zero-order absorption).
In this approach, dose is divided by a fraction of dose absorbed by the zero-order absorption (FR).
Although I used ‘ilogit’ function, however, a range of post-hoc parameter of FR is -1.08 to 2.97.
My first question is how can I code the FR with a range of 0 to 1.
In the second step, I am developing a metabolite PK model with fixing the parameters from parent PK model.
When I use (freeze) function to “error” and “fixef” of parents drug PK parameters, the CV% of metabolite PK parameters is not calculated.
How can I handle these issues?
I’ve attached the model code.
Thanks!
test(){
#------------Parent PK model----------------------------#
dosepoint(A1, duration=(D), bioavail=ilogit(FR))
dosepoint(Aa, bioavail=ilogit(1-FR))
deriv(Aa = -KaAa)
deriv(A1 = - (CL * C)+KaAa )
C = A1 / V
error(CEps(freeze) = 0.544783)
observe(CObs = C * (1 + CEps))
stparm(V = THETA1 * exp(nV)) # Volume of distribution
stparm(CL = THETA2 * exp(nCL)) # CL/F
stparm(D = THETA3 * exp(nD)) # Duration of Parent for zero order absorption to the central compartment
stparm(Ka = THETA4 *exp(nKa)) # First order absorption rate constant
stparm(FR = THETA5 +nFR ) # Fraction of dose directly go to the central compartment with zero order absorption
fixef(THETA1 (freeze)= c(0, 2.98014, ))
fixef(THETA2 (freeze)= c(0, 2.38676, ))
fixef(THETA3 (freeze)= c(0, 0.589064, ))
fixef(THETA4(freeze) = c(0, 0.538162,))
fixef(THETA5(freeze) = c(0, 0.811779,1))
ranef(diag(nV, nCL, nD, nKa, nFR) = c(0.12097657, 0.13467876, 0.1054329, 0.14217843, 3.7403325))
#--------------M1 modeling----------------------------------#
deriv(Am1 = CLC - CLm1Cm1)
Cm1 = Am1/V
observe(CObs_M1 = Cm1 * (1+CEps1))
error(CEps1 = 0.1)
stparm(CLm1 = THETA6 * exp(nCLm1))
fixef(THETA6 = c(0,100,))
ranef(diag(nCLm1) = c(0.1))
}