[NMusers] simulation problem

Dear users,

I am doing a PK-PD simulation with effect compartment model to simulate
the drug concentrations and PD biomarker concentrations simultaneously
under different dose levels. The drug is administered as intravenous
infusion. The PK is a three-compartment model with Michaelis-Menton
elimination from the central compartment, and the PD is the stimulatory
Emax model.

After simulation, I found there is something wrong with the simulated
drug and biomarker concentrations. In general, the simulated drug
concentration-time profiles look good, but there is not always a
consistent increase in the concentration (e.g., Cmax at the end of
infusion) with the increase of the dose. The simulated biomarker
concentrations exhibit an erratic profile. I would very much appreciate
if someone can point out where I am doing wrong in this PK-PD
simulation.

The code is as followings:

$PROB SIMULATE PK AND PD DATA TO SIMPLE PK-LINK-PD MODEL
$DATA DRUG_SIM_3.csv IGNORE=@
$INPUT ID AMT=DOSE RATE TIME DV MDV EVID SEX BSA FLAG CMT
$SUBROUTINES ADVAN6 TOL=5
$MODEL NCOMP = 4
          COMP=(CENTRAL,DEFDOSE,DEFOBS)
          COMP=(PERIPH1)
          COMP=(PERIPH2)
          COMP=(EFFECT)
$PK
         VM = 122*(1+0.502*(2-SEX))*EXP(ETA(1))
         KM = 111*EXP(ETA(7))
         V1 = 8.15*(BSA/1.8)**0.69*EXP(ETA(2))
          V2 = 7.54*EXP(ETA(3))
          V3 = 25.5*EXP(ETA(4))
          Q2 = 5.01*EXP(ETA(5))
          Q3 = 2.74*EXP(ETA(6))
          K12 = Q2/V1
          K21 = Q2/V2
          K13 = Q3/V1
          K31 = Q3/V3
          S1 = V1
;EFF COMP
          K14 = .001*K12
          K40 = THETA(1)*EXP(ETA(8))
          S4 = S1*K14/K40
          EMAX = THETA(2)*EXP(ETA(9))
          C50 = THETA(3)*EXP(ETA(10))
          BSL = THETA(4)*EXP(ETA(11))
          ;OBS = XDV
$DES
       C1 = A(1)/V1
DADT(1) = - A(1)*VM/(KM+C1)- (K12+K13+K14)*A(1)+K21*A(2)+K31*A(3)
       DADT(2) = K12*A(1) - K21*A(2)
       DADT(3) = K13*A(2) - K31*A(3)
       DADT(4) = K14*A(1) - K40*A(4)

$ERROR
TMPC=0
IF(CMT.EQ.1) TMPC=1
TMPE=1-TMPC
       DEL = 0
IF(F.EQ.0) DEL = .000001
IF (TMPC.EQ.1) IPRED = LOG(F + DEL)
IF (TMPC.EQ.1) W=.269
IF (TMPE.EQ.1) IPRED = LOG(BSL*(1+EMAX*F/(C50+F)))
IF (TMPE.EQ.1) W = THETA(5)
IRES = DV-IPRED
IWRES = IRES/W
Y = IPRED+ERR(1)*W
 
$THETA .321 ;1 K40
$THETA 2.75 ; 2 EMAX
$THETA 659 ; 3 C50
$THETA 46.2 ;4 BL
$THETA .267 ;5 W
$OMEGA 0 FIX ;1 VM
$OMEGA 0 FIX ;2 V1
$OMEGA 0 FIX ;3 V2
$OMEGA 0 FIX ;4 V3
$OMEGA 0 FIX ;5 Q2
$OMEGA 0 FIX ;6 Q3
$OMEGA 0 FIX ;7 KM
$OMEGA 0 FIX ;8 K40
$OMEGA 0 FIX ;9 EMAX
$OMEGA 0 FIX ;10 C50
$OMEGA 0 FIX ;11 BSL
$SIGMA 1 FIX
$SIMULATION (9215690) ;seed 1-7 digits
$TAB ID AMT TIME DV SEX BSA CMT ONEHEADER NOPRINT FILE=mytab14

The datafile for the first three subjects is as the following:

#ID AMT RATE TIME DV MDV EVID SEX BSA FLAG CMT
1 354 1074 0 . 1 1 1 1.8 0 1
1 0 0 0 . 0 0 1 1.8 3 4
1 0 0 0.33 . 0 0 1 1.8 2 1
1 0 0 0.33 . 0 0 1 1.8 3 4
1 0 0 1 . 0 0 1 1.8 2 1
1 0 0 1 . 0 0 1 1.8 3 4
1 0 0 2 . 0 0 1 1.8 2 1
1 0 0 2 . 0 0 1 1.8 3 4
1 0 0 4 . 0 0 1 1.8 2 1
1 0 0 4 . 0 0 1 1.8 3 4
1 0 0 8 . 0 0 1 1.8 2 1
1 0 0 8 . 0 0 1 1.8 3 4
1 0 0 12 . 0 0 1 1.8 2 1
1 0 0 12 . 0 0 1 1.8 3 4
1 0 0 24 . 0 0 1 1.8 2 1
1 0 0 24 . 0 0 1 1.8 3 4
1 0 0 48 . 0 0 1 1.8 2 1
1 0 0 48 . 0 0 1 1.8 3 4
2 709
2149 0 . 1 1 1 1.8 0 1
2 0 0 0 . 0 0 1 1.8 3 4
2 0 0 0.33 . 0 0 1 1.8 2 1
2 0 0 0.33 . 0 0 1 1.8 3 4
2 0 0 1 . 0 0 1 1.8 2 1
2 0 0 1 . 0 0 1 1.8 3 4
2 0 0 2 . 0 0 1 1.8 2 1
2 0 0 2 . 0 0 1 1.8 3 4
2 0 0 4 . 0 0 1 1.8 2 1
2 0 0 4 . 0 0 1 1.8 3 4
2 0 0 8 . 0 0 1 1.8 2 1
2 0 0 8 . 0 0 1 1.8 3 4
2 0 0 12 . 0 0 1 1.8 2 1
2 0 0 12 . 0 0 1 1.8 3 4
2 0 0 24 . 0 0 1 1.8 2 1
2 0 0 24 . 0 0 1 1.8 3 4
2 0 0 48 . 0 0 1 1.8 2 1
2 0 0 48 . 0 0 1 1.8 3 4
3 1418 4298 0 . 1 1 1 1.8 0 1
3 0 0 0 . 0 0 1 1.8 3 4
3 0 0 0.33 . 0 0 1 1.8 2 1
3 0 0 0.33 . 0 0 1 1.8 3 4
3 0 0 1 . 0 0 1 1.8 2 1
3 0 0 1 . 0 0 1 1.8 3 4
3 0 0 2 . 0 0 1 1.8 2 1
3 0 0 2 . 0 0 1 1.8 3 4
3 0 0 4 . 0 0 1 1.8 2 1
3 0 0 4 . 0 0 1 1.8 3 4
3 0 0 8 . 0 0 1 1.8 2 1
3 0 0 8 . 0 0 1 1.8 3 4
3 0 0 12 . 0 0 1 1.8 2 1
3 0 0 12 . 0 0 1 1.8 3 4
3 0 0 24 . 0 0 1 1.8 2 1
3 0 0 24 . 0 0 1 1.8 3 4
3 0 0 48 . 0 0 1 1.8 2 1
3 0 0 48 . 0 0 1 1.8 3 4

Thanks in advance!

Jing
Received on Wed Nov 22 2006 - 12:30:34 EST