Re: [NMusers] simulation problem

Hi Jing:
I think it is because of the random error. It is already very near the
baseline. When I fixed your SIGMA1 to zero, I got about the same
values for time 0, 24 and 48 hr.

Best regards,
Sam Liao
Pharmax Research
> Hi Sam,
>
> Thanks for the corrections! However, the corrected model does not look
> very helpful for the simulated PD biomarker concentrations. Here I am
> attaching the simulated biomarker concentration-time profiles for you to
> review. I don't understand why the biomarker concentrations increased
> again at 48 h in some subjects and there is not an apparent
> dose-dependent response.
>
> Any thoughts? Thanks again.
>
> Jing
>
>
>>>> Sam Liao <sliao_at_pharmaxresearch.com> 11/22/06 4:40 PM >>>
>>>>
> Hi Jing:
>
> I tried your model and I think there are few minor corrections needed in
>
> your model as shown below:
>
> $DES
> C1 = A(1)/V1
> DADT(1) = - C1*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(1) - K31*A(3)
> DADT(4) = K14*A(1) - K40*A(4)
>
> I used C1 instead of A(1) in the first term of DADT(1).
> I replaced K13*A(2) with K13*A(1) in the first term of DADT(3). Hope
> this will work for you.
>
> Best regards,
> Sam Liao
> Pharmax Research
>
>> 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
>>
>>
>>
>>
>>
>
>
>