Fitting 2 compartment first-order input PK/PD model.
From: "Wixley, Dick" <Dick.Wixley@solvay.com>
Subject: Fitting 2 compartment first-order input PK/PD model.
Date: Tue, 14 Sep 1999 10:56:41 +0200
Dear NONMEM users,
I have used the following code to successfully fit a 2-compartmental model with first order input to data from 18 subjects.(exhibit 1).
I now wish to fit a PD emax link model to the PD effect QT. From reading the NONMEM manuals I understand that to do this I should use ADVAN7. This I have tried to do using various combinations of what seems reasonable. I attach one example (exhibit 2), and the input file with PK parameters and the new DV=QT (exibit 3). The output is garbage so I suspect that my input was also.
Thank you for your help in advance.
Dick Wixley.
-----------------------------------------------------------------
exhibit(1)
----------
$PROBLEM 50 bid dose CrY_U_21 unstr. COV
$INPUT
SUBJ=ID DOSE=AMT DAYT=DATE TIME CPLA=DV DDOS EVID MDV QT QTC HRT OLD
$DATA y:\nonmx\tEDRdY.TXT IGNORE=C
$SUBROUTINES ADVAN4 TRANS1
$PK
K =THETA(1)*EXP((ETA(1)))
K23=THETA(2)*EXP((ETA(2)))
K32=THETA(3)*EXP((ETA(3)))
V =THETA(4)*EXP((ETA(4)))
KA=THETA(5)*EXP((ETA(5)))
S2=V /1000
$ERROR
FX=0
IF(F.EQ.0) FX=1
W=F+FX
Y=F+F*ERR(1)+ERR(2)
IPRED=F
IRES=DV-IPRED
IWRES=IRES/W
$THETA (0,.254) (0,.09) (0,.1) (0,174) (0,2.64)
$OMEGA BLOCK(5) 1.66 5 22.5 3.74 15 11 0.2 2 1.7 1.2
1.6 8.5 6.3 2.3 5.72
$SIGMA 0.25 10
$ESTIMATION MAXEVAL=9999 PRINT=6 SIGDIGITS=6 POSTHOC MSFO=RUN5K.MSF
$COVARIANCE
$TABLE ID TIME DOSE K K23 K32 V KA QT QTC HRT OLD
IPRED IRES IWRES NOPRINT FILE=ORY_U_21 ONEHEADER
-----------------------------------------------------------------
exhibit(2)
----------
$PROBLEM 50 bid dose CrYDU_21 unstr. COV
$INPUT
SUBJ=ID TIME DOSE=AMT AK A23 A32 AV AKA EVID MDV QT=DV QTC HRT old
$DATA y:\nonmx\ZRY_U_21 IGNORE=C
$SUBROUTINES ADVAN7
$MODEL NCOMPARTMENTS=4 NPARAMETERS=6
COMP=(DEPOT DEFDOSE INITIALOFF) COMP=(CENTRAL ) COMP=(PERIP)
COMP=(EFFECT DEFOBS)
$PK
K12=AK
K23=A23
K32=A32
V=AV
KA=AKA
K40 =THETA(1)*EXP((ETA(1)))
K24=.001*K40
S2=V /1000
$ERROR
EMAX = THETA(2)
C50 = THETA(3)
E = EMAX*F/(F+C50)
Y=E*(1+ERR(1))
IPRED=E
IRES=DV-IPRED
$THETA (0,1) (0,1) (0,1)
$OMEGA 0.25
$SIGMA 0.25
$ESTIMATION MAXEVAL=9999 PRINT=6 SIGDIGITS=6 POSTHOC MSFO=RUN5K.MSF
$COVARIANCE
$TABLE ID TIME DOSE K12 K23 K32 V KA EMAX C50 K40 IPRED IRES NOPRINT
FILE=ORYDU_21 ONEHEADER
-----------------------------------------------------------------
exhibit(3)
----------
19 0 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 12 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.341 0.355 65 0
19 12 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 24 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 36 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.335 0.359 69 0
19 36 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 48 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 60 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.338 0.362 69 0
19 60 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 72 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 84 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.36 0.375 65 0
19 84 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 96 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 108 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.345 0.362 66 0
19 108 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 120 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 132 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.315 0.361 79 0
19 132 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 144 39.9 0.24981 0.06219 0.028924 49.856 0.53846 1 1 0 0 0 0
19 145.5 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.36 0.363 61 0
19 147 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.375 0.369 58 0
19 149 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.356 0.353 59 0
19 156 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.339 0.358 67 0
19 168 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.349 0.349 60 0
19 192 0 0.24981 0.06219 0.028924 49.856 0.53846 0 0 0.33 0.379 79 0
20 0 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0
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20 36 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0
20 48 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0
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20 60 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0
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20 84 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0
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20 108 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0
20 120 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0
20 132 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.374 0.395 67 0
20 132 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0
20 144 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0
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21 0 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 12 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.368 0.386 66 0
21 12 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 24 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 36 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.354 0.382 70 0
21 36 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 48 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 60 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.357 0.396 74 0
21 60 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 72 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 84 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.38 0.392 64 0
21 84 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 96 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 108 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.374 0.377 61 0
21 108 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
21 120 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
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21 132 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0
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21 192 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.368 0.383 65 0
22 0 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
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22 12 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 24 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 36 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.367 0.385 66 0
22 36 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 48 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 60 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.366 0.378 64 0
22 60 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 72 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 84 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.346 0.376 71 0
22 84 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 96 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 108 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.356 0.373 66 0
22 108 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 120 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 132 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.362 0.38 66 0
22 132 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 144 39.9 0.25904 0.055188 0.015821 52.394 0.62011 1 1 0 0 0 0
22 145.5 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.394 0.384 57 0
22 147 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.394 0.374 54 0
22 149 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.391 0.384 58 0
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22 192 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.36 0.369 63 0
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23 12 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
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23 36 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
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23 60 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
23 72 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
23 84 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.383 0.36 53 0
23 84 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
23 96 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
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23 108 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
23 120 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
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23 132 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
23 144 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0
23 145.5 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.439 0.358 40 0
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23 156 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.373 0.354 54 0
23 168 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.389 0.341 46 0
23 192 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.372 0.333 48 0
24 0 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 12 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.372 0.399 69 0
24 12 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 24 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
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24 36 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 48 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 60 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.346 0.376 71 0
24 60 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 72 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
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24 84 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 96 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 108 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.362 0.368 62 0
24 108 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 120 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 132 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.323 0.387 86 0
24 132 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 144 39.9 0.27188 0.081161 0.059445 56.79 0.56839 1 1 0 0 0 0
24 145.5 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.382 0.369 56 0
24 147 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.4 0.379 54 0
24 149 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.372 0.372 60 0
24 156 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.34 0.388 78 0
24 168 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.352 0.364 64 0
24 192 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.345 0.362 66 0
25 0 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
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25 12 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 24 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 36 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.393 0.406 64 0
25 36 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 48 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 60 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.383 0.411 69 0
25 60 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 72 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 84 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.393 0.409 65 0
25 84 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 96 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 108 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.357 0.388 71 0
25 108 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 120 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
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25 132 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
25 144 39.9 0.23012 0.039867 0.04863 91.039 0.85075 1 1 0 0 0 0
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25 147 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.464 0.419 49 0
25 149 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.392 0.417 68 0
25 156 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.406 0.413 62 0
25 168 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.428 0.402 53 0
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26 0 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 12 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.342 0.407 85 0
26 12 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 24 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 36 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.338 0.38 76 0
26 36 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 48 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 60 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.356 0.395 74 0
26 60 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 72 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 84 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.328 0.417 97 0
26 84 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 96 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 108 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.346 0.397 79 0
26 108 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 120 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 132 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.342 0.407 85 0
26 132 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 144 39.9 0.2399 0.020742 0.031824 111.77 0.77498 1 1 0 0 0 0
26 145.5 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.389 0.389 60 0
26 147 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.398 0.414 65 0
26 149 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.372 0.424 78 0
26 156 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.339 0.417 91 0
26 168 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.38 0.402 67 0
26 192 0 0.2399 0.020742 0.031824 111.77 0.77498 0 0 0.356 0.408 79 0
27 0 39.9 0.30741 0.034899 0.033048 74.992 0.48206 1 1 0 0 0 0
27 12 0 0.30741 0.034899 0.033048 74.992 0.48206 0 0 0.372 0.393 67 0
27 12 39.9 0.30741 0.034899 0.033048 74.992 0.48206 1 1 0 0 0 0
27 24 39.9 0.30741 0.034899 0.033048 74.992 0.48206 1 1 0 0 0 0
27 36 0 0.30741 0.034899 0.033048 74.992 0.48206 0 0 0.375 0.396 67 0
27 36 39.9 0.30741 0.034899 0.033048 74.992 0.48206 1 1 0 0 0 0
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36 147 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.395 0.424 69 0
36 149 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.382 0.41 69 0
36 156 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.347 0.423 89 0
36 168 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.371 0.395 68 0
36 192 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.358 0.411 79 0
-----------------------------------------------------------------------END*