From: "atul" <bvatul@ufl.edu>
Subject: Simulation of coinfused drugs
Date: Fri, 5 Oct 2001 00:19:17 -0700

Hello All

Could somebody help in this?

I am analysing a data set in which two drugs are coadministered (one intramuscular and one as intravenous). I have the data of two Pharmacodynamic markers (One is precursor and one is reflective of the effect). This could be setup in NONMEM (Thanks to Dr Holford and Jogarao). But when I am trying to run first a simulation I am facing a strange problem. I am not sure if this is a problem of arranging a data set or anyother thing in the code. The data of the intramuscular drug could be well simulated. I did fit the data of the both the drugs seperately and used those parameters in the complete model (ie., including both the drugs in one model) for simulation. But surprisingly the data of the second drug is not being simulated correctly. It is totally off. Where could the mistake be? I am writing below the code, one volunteer data set and the output.

$PROBLEM ANALYSIS OF POP DATA
$INPUT ID TIME DV AMT RATE CMT XVID ADV
$DATA TOTAL.CSV IGNORE=3DC
$SUBROUTINES ADVAN6 TRAN 1 TOL=3D3

$MODEL
COMP=3D(1); DRUG (IM, DOSING CMT) 1
COMP=3D(2); DRUG (IM), 2
COMP=3D(3); DRUG (IM), PERIPHERAL,3
COMP=3D(4); DRUG 2 (IV INFUSION), 4
COMP=3D(5); MARKER1 5
COMP=3D(6); MARKER2 6

$ABBREVIATED DERIV2=3DNO
$PK
TVCL2=3DTHETA(1)
TVCL4=3DTHETA(2)
TVV2=3DTHETA(3)
TVV4=3DTHETA(4)
TVK23=3DTHETA(5)
TVK32=3DTHETA(6)
TVK0=3DTHETA(7)
TVKG=3DTHETA(8)
TVKGL=3DTHETA(9)
TVKL=3DTHETA(10)
TSMAX1=3DTHETA(11)
TSMAX2=3DTHETA(12)
TSC501=3DTHETA(13)
TSC502=3DTHETA(14)
TVKA=3DTHETA(15)
CL2=3DTVCL2*EXP(ETA(1))
CL4=3DTVCL4*EXP(ETA(2))
V2=3DTVV2*EXP(ETA(3))
V4=3DTVV4*EXP(ETA(4))
K23=3DTVK23*EXP(ETA(5))
K32=3DTVK32*EXP(ETA(6))
K0=3DTVK0*EXP(ETA(7))
KG=3DTVKG*EXP(ETA(8))
KGL=3DTVKGL*EXP(ETA(9))
KL=3DTVKL*EXP(ETA(10))
SMAX1=3DTSMAX1*EXP(ETA(11))
SMAX2=3DTSMAX2*EXP(ETA(12))
SC501=3DTSC501*EXP(ETA(13))
SC502=3DTSC502*EXP(ETA(14))
KA=3DTVKA*EXP(ETA(15))
F5=3DK0/(KGL+KG)
F6=3DF5*KGL/KL

$DES
K20=3DCL2/V2
K40=3DCL4/V4
S2=3DV2/1000
S4=3DV4/1000
DADT(1)=3D-KA*A(1)
DADT(2)=3DKA*A(1)-(K20+K23)*A(2)+K32*A(3)
DADT(3)=3DK23*A(2)-K32*A(3)
DADT(4)=3D-K40*A(4)
Q=3DA(2)/S2
D=3DA(4)/S4
PR=3DA(5)
L=3DA(6)
EG=3D1+(SMAX1*Q/(SC501+Q))
ED=3D1+(SMAX2*D/(SC502+D))
DADT(5)=3DK0-KG*EG*PR-KGL*PR
DADT(6)=3DKGL*PR-KL*ED*L=20

$THETA =20
(0.05); CL2=20
(0.09); CL4=20
(0.65); V2
(0.37); V4
(0.1); K23=20
(0.2);(1.46); K32
(3); K0
(0.1); KG=20
(0.135); KGL
(0.219) ; KOUT
(6); SMAX1
(4); SMAX2
(250); SC501
(200); SC502
(3.5); KA

$OMEGA
(0.1); CL2=20
(0.1); CL4=20
(0.1); V2
(0.1); V4
(0.1); K23=20
(0.1); K32
(0.1); K0
(0.1); KG=20
(0.1); KGL
(0.1) ; KL
(0.1); SMAX1
(0.1); SMAX2
(0.1); SC501
(0.1); SC502
(0.1); KA

$ERROR
Q1=3D0
IF(CMT.EQ.2) Q1=3D1
Y1=3DF*EXP(ERR(1))
Q2=3D0
IF(CMT.EQ.4) Q2=3D1
Y2=3DF*EXP(ERR(2))
Q3=3D0
IF(CMT.EQ.5) Q3=3D1
Y3=3DF*EXP(ERR(3))
Q4=3D0
IF(CMT.EQ.6) Q4=3D1
Y4=3DF*EXP(ERR(4))
Y=3DQ1*Y1+Q2*Y2+Q3*Y3+Q4*Y4
IPRED=3DF
IRES=3DDV-IPRED

$SIGMA
(0.1)
(0.1)
(0.1)
(0.1)

$SIMULATION(34567892) ONLYSIMUL

$TABLE ID TIME CMT ADV NOPRINT ONEHEADER FILE=3Dsdtab100

This is input file

CID TIME DV AMT RATE CMT EVID ADV
1 0 0 20 0 1 1 0
1 0 0 50 294.117 4 1 0
1 0 0 1 0 5 0 0
1 0 0 1 0 6 0 0
1 0 0 0 0 5 0 0
1 0 0 0 0 6 0 0
1 0.33 0 0 0 2 0 7.04
1 0.33 0 0 0 5 0 6.21
1 0.33 0 0 0 6 0 5.64
1 0.9 0 0 0 4 0 154.38
1 1.07 0 0 0 2 0 15.37
1 1.07 0 0 0 5 0 7.29
1 1.07 0 0 0 6 0 8.14
1 1.28 0 0 0 2 0 14.49
1 1.28 0 0 0 5 0 8.26
1 1.28 0 0 0 6 0 6.67

This is the output I observe:

ID TIME CMT ADV DV PRED RES WRES
1 0 1 0 0 0 0 0
1 0 4 0 0 20 0 0
1 0 5 0 0 20 0 0
1 0 6 0 0 20 0 0
1 0 5 0 21.728 12.766 8.9624 0
1 0 6 0 6.961 7.8694 -0.90846 0
1 0.33 2 7.04 14.208 13.24 0.96858 0
1 0.33 5 6.21 15.613 10.634 4.9788 0
1 0.33 6 5.64 7.3812 5.9263 1.4549 0
1 0.9 4 154.38 37.967 41.011 -3.0444 0
1 1.07 2 15.37 44.333 17.051 27.282 0
1 1.07 5 7.29 14.821 7.417 7.4042 0
1 1.07 6 8.14 2.0347 3.231 -1.1963 0
1 1.28 2 14.49 22.685 16.732 5.953 0
1 1.28 5 8.26 7.7295 6.8097 0.91976 0
1 1.28 6 6.67 1.6718 2.7479 -1.0761 0

The column ADV stands for actual experimental values. Please note that values for CMT=3D4 are not predicted correctly. It might appear that it is a single value. But when I fit the data using ADVAN 6 it gives me a predicted value of 150. So starting parameters are fine for simulations. Also I was observing that writing EVID in the control stream did not run simulations. but when it was coded as XVID it did run. Am I making any mistake? I did run simulations in the past but never encountered this type of problem in coding as EVID and XVID. ALso initialization for CMT=3D5 and 6 shows a value of 20 (This is strange). Why?? Is it necessary to reset the dose event?

Please let me know your suggestions and correct me if I am wrong anywhere.

Thanks in advance for your time

Atul