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 20 12 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.366 0.409 75 0 20 12 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0 20 24 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0 20 36 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.375 0.39 65 0 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 20 60 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.388 0.381 58 0 20 60 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0 20 72 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0 20 84 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.378 0.384 62 0 20 84 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0 20 96 39.9 0.26484 0.055298 0.0086657 45.171 0.59655 1 1 0 0 0 0 20 108 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.396 0.376 54 0 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 20 145.5 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.428 0.383 48 0 20 147 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.44 0.398 49 0 20 149 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.406 0.385 54 0 20 156 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.399 0.385 56 0 20 168 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.387 0.371 55 0 20 192 0 0.26484 0.055298 0.0086657 45.171 0.59655 0 0 0.382 0.379 59 0 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 21 132 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.351 0.385 72 0 21 132 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0 21 144 39.9 0.27192 0.067583 0.060692 69.26 0.65598 1 1 0 0 0 0 21 145.5 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.414 0.393 54 0 21 147 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.398 0.401 61 0 21 149 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.423 0.398 53 0 21 156 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.366 0.384 66 0 21 168 0 0.27192 0.067583 0.060692 69.26 0.65598 0 0 0.383 0.377 58 0 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 22 12 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.354 0.38 69 0 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 22 156 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.472 0.476 61 0 22 168 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.358 0.364 62 0 22 192 0 0.25904 0.055188 0.015821 52.394 0.62011 0 0 0.36 0.369 63 0 23 0 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0 23 12 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.377 0.377 60 0 23 12 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0 23 24 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0 23 36 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.374 0.368 58 0 23 36 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0 23 48 39.9 0.25582 0.070004 0.032757 53.361 0.60582 1 1 0 0 0 0 23 60 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.355 0.364 63 0 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 23 108 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.37 0.341 51 0 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 23 132 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.352 0.343 57 0 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 23 147 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.422 0.361 44 0 23 149 0 0.25582 0.070004 0.032757 53.361 0.60582 0 0 0.393 0.362 51 0 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 24 36 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.352 0.396 76 0 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 24 84 0 0.27188 0.081161 0.059445 56.79 0.56839 0 0 0.359 0.391 71 0 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 25 12 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.371 0.406 72 0 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 25 132 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.375 0.408 71 0 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 25 145.5 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.453 0.422 52 0 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 25 192 0 0.23012 0.039867 0.04863 91.039 0.85075 0 0 0.4 0.386 56 0 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 27 48 39.9 0.30741 0.034899 0.033048 74.992 0.48206 1 1 0 0 0 0 27 60 0 0.30741 0.034899 0.033048 74.992 0.48206 0 0 0.379 0.391 64 0 27 60 39.9 0.30741 0.034899 0.033048 74.992 0.48206 1 1 0 0 0 0 27 72 39.9 0.30741 0.034899 0.033048 74.992 0.48206 1 1 0 0 0 0 27 84 0 0.30741 0.034899 0.033048 74.992 0.48206 0 0 0.359 0.371 64 0 27 84 39.9 0.30741 0.034899 0.033048 74.992 0.48206 1 1 0 0 0 0 27 96 39.9 0.30741 0.034899 0.033048 74.992 0.48206 1 1 0 0 0 0 27 108 0 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34 147 0 0.31527 0.072413 0.044611 66.156 0.60754 0 0 0.463 0.405 46 0 34 149 0 0.31527 0.072413 0.044611 66.156 0.60754 0 0 0.443 0.412 52 0 34 156 0 0.31527 0.072413 0.044611 66.156 0.60754 0 0 0.423 0.412 57 0 34 168 0 0.31527 0.072413 0.044611 66.156 0.60754 0 0 0.422 0.411 57 0 34 192 0 0.31527 0.072413 0.044611 66.156 0.60754 0 0 0.39 0.396 62 0 35 0 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 12 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.353 0.415 83 0 35 12 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 24 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 36 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.351 0.405 80 0 35 36 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 48 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 60 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.362 0.41 77 0 35 60 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 72 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 84 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.353 0.413 82 0 35 84 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 96 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 108 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.351 0.398 77 0 35 108 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 120 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 132 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.351 0.403 79 0 35 132 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 144 39.9 0.29731 0.048905 0.030071 57.701 0.45381 1 1 0 0 0 0 35 145.5 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.417 0.399 55 0 35 147 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.435 0.453 65 0 35 149 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.37 0.402 71 0 35 156 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.352 0.414 83 0 35 168 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.369 0.396 69 0 35 192 0 0.29731 0.048905 0.030071 57.701 0.45381 0 0 0.381 0.384 61 0 36 0 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 12 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.352 0.416 84 0 36 12 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 24 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 36 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.357 0.417 82 0 36 36 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 48 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 60 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.36 0.423 83 0 36 60 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 72 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 84 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.354 0.431 89 0 36 84 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 96 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 108 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.356 0.421 84 0 36 108 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 120 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 132 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.351 0.415 84 0 36 132 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 144 39.9 0.2167 0.063139 0.062378 83.023 1.0294 1 1 0 0 0 0 36 145.5 0 0.2167 0.063139 0.062378 83.023 1.0294 0 0 0.402 0.415 64 0 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*

Date: Tue, 14 Sep 1999 09:57:35 -0400 (EDT) From: Jogarao Gobburu 301-594-5661 FAX 301-480-8329 <GOBBURUJ@cder.fda.gov> Subject: Re: Fitting 2 compartment first-order input PK/PD model. Hello, 1. Firstly, I would suggest that you parameterize your PK model using clearances and volumes of distribution. This way, you can interpret the inter-individual variability better. 2. After you finalize your PK model, try to simulate the concentration first to check whether the PK coding in your PD model is correct. Output Cp=A(2)/S2. 3. It may be a good idea to output ONEHEADER in your $TABLE record, for easy identification. 4. You should have a k20 for the elimination of drug from the central compartment. 5. The assumption when using link model is that negligible amount of drug enters the effect site, hence k24 = 0.001*k20 may be more meaningful. 6. Generally, effects of drugs on QT may be quite instantaneous. You might want to check if you need a distrbutional delay model in the first place. Hope this helps ! Regards, Joga Gobburu Pharmacometrics, CDER, FDA.

From: "Piotrovskij, Vladimir [JanBe]" <VPIOTROV@janbe.jnj.com> Subject: RE: Fitting 2 compartment first-order input PK/PD model. Date: Tue, 14 Sep 1999 16:28:55 +0200 Dick, Effect compartment concentration for the 2-comp model with 1st-order input can be easily obtained analytically. You should not use ADVAN7 since it is inefficient. If you want I can try to find a control example in my archive and send you. Best regards, Vladimir ---------------------------------------------------------------------- Vladimir Piotrovsky, Ph.D. Janssen Research Foundation Clinical Pharmacokinetics B-2340 Beerse Belgium Email: vpiotrov@janbe.jnj.com All statements in this message represent the opinions of the author and do not necessarily reflect official policy or position of the employer.

Date: Tue, 14 Sep 1999 09:50:28 -0500 From: sras1256 <sras1256@postoffice.uri.edu> Subject: RE: Fitting 2 compartment first-order input PK/PD model. Dear Dick, you can use Advan 3 to fit a 2-comp model. The PK model will be the first comp, and the PD model will be the second comp. Keo(for the effect comp) will be K21. Using exponentail model for inter-individual variability, you have to use FOCE method to estimate your PK/PD parameters correctly. By the way I did use Sigmoid Emax model with effect comp, using Advan 3, but each run took up to 2-3 hours, may be yours will be faster because you do not have gamma in the Emax model. Hope that will help. Best regards, Suzette Rashed-Girgis, MSc University of Rhode Island

Date: Tue, 14 Sep 1999 11:19:26 -0700 (PDT) From: ABoeckmann <alison@c255.ucsf.edu> Subject: Re: Fitting 2 compartment first-order input PK/PD model. Thanks to everyone for helpful comments on Dick Wixley's question. Joga's points are especially good ones. A few other remarks: 1) "The output is garbage so I suspect that my input was also." Then why include these? $ESTIMATION MAXEVAL=9999 PRINT=6 SIGDIGITS=6 POSTHOC MSFO=RUN5K.MSF $COVARIANCE Start slowly. Omit the $ESTIMATION record. Look first at the predictions with the initial ests. of theta. If the model is wrong, the Estimation Step will distort the thetas. You won't be able to tell if the predictions are garbage because of the bad thetas or the bad model. This advice is for everyone!!!! 2) As Joga pointed out, there appear to be modelling errors. Probably "K12=AK" should be "K12=AKA" and "K20=AK" is missing. 3) If you do not need elimination from the effect compartment, use ADVAN12. This will give you compt 4 to use as the effect compartment, and is faster than ADVAN7. Alison

Date: Tue, 14 Sep 1999 16:02:23 -0700 From: LSheiner <lewis@c255.ucsf.edu> Subject: Re: Fitting 2 compartment first-order input PK/PD model. >From all the answers, I gather that most of you-all don't know that there are a set of control streams for analysing PK/PD data that are used for the Intermed NONMEM course. They are a little old, but still serviceable .. They can be found at ftp://pkpd.icon.palo-alto.med.va.gov/nonmem.dir/PKPD.DIR/ LBS. Lewis B Sheiner, MD Professor: Lab. Med., Biopharm. Sci., Med. Box 0626 voice: 415 476 1965 UCSF, SF, CA fax: 415 476 2796 94143-0626 email: lewis@c255.ucsf.edu

From: "Wixley, Dick" <Dick.Wixley@solvay.com> Subject: RE: Fitting 2 compartment first-order input PK/PD model. Date: Wed, 15 Sep 1999 09:46:15 +0200 Dear All Thank you all very much for your helpful comments. My question has been more than adequately answered. Dick Wixley