Phenobarbital_PML

Phenobarbital PML example

This example illustrates simple PK modeling for a one-compartment model with Cl (clearance) and V (volume) parameterization, and multiple doses per subject.

Data

The subject data are contained in an ASCII file (*.dat). The headers and the first subject data read as follows:

pheno.dat 
  ## xid time dose  wt  apgr yobs
      1   0.0 25.0  1.4  7     .
      1   2.0   .   1.4  7   17.3
      1  12.5  3.5  1.4  7     .
      1  24.5  3.5  1.4  7     .
      1  37.0  3.5  1.4  7     .
      1  48.0  3.5  1.4  7     .
      1  60.5  3.5  1.4  7     .
      1  72.5  3.5  1.4  7     .
      1  85.3  3.5  1.4  7     .
      1  96.5  3.5  1.4  7     .
      1 108.5  3.5  1.4  7     .
      1 112.5   .   1.4  7   31.0

Column mappings

The ASCII file containing column mappings reads as follows.

   colspheno.txt 
   id(xid)
   time(time)
   dose(a <- dose)
   covr(wt <- wt)
   obs(cObs <- yobs)

The model

The PML model file reads as follows.

phenophxexam.mdl 
  # One compartment model with IV bolus dosing
  # Cl, V parameterization with differential equation 
  # formulation
  Pheno(){
     dosepoint(a)
     covariate(wt)  #wt is a covariate for Cl and V
     deriv(a=-a*Cl/V)
     c=a/V
     fixef(
        tvCl=c(0, 0.0001,)
        wtCl=c(0, 0.005,)
        tvV=c(0, 0.1,)
        wtV=c(0, 1,)
        )
     ranef(
        diag(nCl, nV)=c(0.1, 0.1,)
        )
     stparm(
        Cl=(tvCl+wtCl*wt)*exp(nCl)
        V=(tvV+wtV*wt)*exp(nV)
        )
  #NONMEM initial estimate for sigma variance is 10
  #Phoenix initial estimate represents a standard deviation
  #rather than a variance, so the equivalent initial estimate is
  #eps1=sqrt(10)=3.16
  #  error(eps1=3.16)
  #  observe(cObs=c+eps1) 
  }

NONMEM control file

The equivalent model, written as a NONMEM control file (*.ctl), would read as follows.

  $PROBLEM PHENOBARB SIMPLE MODEL
  $INPUT ID TIME AMT WGT APGR DV
  $DATA pheno.dat
  $SUBR ADVAN6 
  $MODEL COMP=(CENTRAL,DEFOBS,NOOFF)
  $PK
     TVCL=THETA(1)+WGT*THETA(2)
     TVV=THETA(3)+WGT*THETA(4)
     CL=TVCL*EXP(ETA(1))
     V=TVV*EXP(ETA(2))
     S1=V
  $THETA(0, 0.0001,)(0, 0.005,)(0, .1,)(0, 1,)
  $OMEGA .1 .1
  $DES 
     DADT(1)=-CL/V*A(1)
  $ERROR
     Y=F+EPS(1)
  $SIGMA 10
  $ESTIMATION METHOD=1 PRINT=5 POSTHOC