INCLUDE Functionality and Multiple-Dose Data

Dears, I was testing out the following code, presented by Tom at a meeting a while back, for independent estimation of individual PK data. The code works just fine with Single dose data, even when there are multiple periods, but it fails to analyze the true "multiple dose" data. For the single dose cross-over studies, I have used both EVID=1 or EVID=4 for the second and all subsequent doses...and both approaches work fine. However, when I try to analyze multiple-dose data, the code does not work anymore. It analyzes the first subject but fails to pick up the second subject etc... I was wondering whether it is possible to use similar method to analyze multiple dose data! BTW, I am running this on NM7, but it also works fine under NM6. I have attached the Model file below and excerpts from the output of failed run is also attached... Thanks for your suggestions in advance. On behalf of Dr. Partha Nandy Mahesh Kind Regards, Partha Nandy E-Mail: [email protected]. ************************************************************************ ************************************************************************ ********* Model File $PROB RUN# xxx $INPUT C ID STUY SUBJ EVID RATE=DROP AMT ADDL II TIME DV LOGC MDV $DATA xxx.csv RECS=ID $SUBROUTINES ADVAN4 TRANS4 $PK KA=THETA(1) CL=THETA(2) V2=THETA(3) Q=THETA(4) V3=THETA(5) ALAG1=THETA(6) S2=V2/1000 $ERROR Y=F + F*ERR(1) $THETA (.1, 1.97, 10) ;[KA] (25, 516, 3000) ;[CL] (50, 625, 3000) ;[V2] (1, 40, 500) ;[Q] (100, 900,20000) ;[V3] (0, 0.336, 1.2) ;[ALAG1] $OMEGA 0.05 ;[P] $EST METHOD=0 MAXEVAL=9999 PRINT=0 NOABORT SIGDIGITS=4 $COVARIANCE SPECIAL PRINT=E $TABLE ID SUBJ TIME NOPRINT ONEHEADER FILE=xxx.tab NCLUDE xxx2.txt 128 $PROB RUN# xxx2 $INPUT C ID STUY SUBJ EVID RATE=DROP AMT ADDL II TIME DV LOGC MDV $DATA xxx.csv RECS=ID NOREWIND $THETA (.1, 1.97, 10) ;[KA] (25, 516, 3000) ;[CL] (50, 625, 3000) ;[V2] (1, 40, 500) ;[Q] (100, 900,20000) ;[V3] (0, 0.336, 1.2) ;[ALAG1] $OMEGA 0.05 ;[P] PROPORTIONAL COMPONENT $EST METHOD=0 MAXEVAL=9999 PRINT=0 NOABORT SIGDIGITS=4 $COVARIANCE SPECIAL PRINT=E $TABLE ID SUBJ TIME NOPRINT NOHEADER FORWARD FILE=xxx.tab [Nandy, Partha [PRDUS]] Excerpts from the Output of Failed Run: [Nandy, Partha [PRDUS]] ID=1 TABLE NO. 1 STDY ID TIME IPRE EVID CMT IRES K14 CL V2 V3 K23 K32 TSLD FOOD OCC IRES IWRES DV PRED RES WRES 6.0000E+00 6.0100E+02 0.0000E+00 0.0000E+00 1.0000E+00 1.0000E+00 0.0000E+00 1.2891E+00 7.3703E+02 8.4859E+02 1.3007E+03 3.4662E-01 2.2614E-01 0.0000E+00 3.0000E+00 1.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 6.0000E+00 6.0100E+02 0.0000E+00 0.0000E+00 2.0000E+00 2.0000E+00 0.0000E+00 1.2891E+00 7.3703E+02 8.4859E+02 1.3007E+03 3.4662E-01 2.2614E-01 0.0000E+00 3.0000E+00 1.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 6.0000E+00 6.0100E+02 2.3300E-01 0.0000E+00 2.0000E+00 2.0000E+00 0.0000E+00 1.2891E+00 7.3703E+02 8.4859E+02 1.3007E+03 3.4662E-01 2.2614E-01 2.3300E-01 3.0000E+00 1.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 1.1523E+02 0.0000E+00 0.0000E+00 ID=2 TABLE NO. 1 STDY ID TIME IPRE EVID CMT IRES K14 CL V2 V3 K23 K32 TSLD FOOD OCC IRES IWRES DV PRED RES WRES 6.0000E+00 6.0200E+02 0.0000E+00 0.0000E+00 1.0000E+00 1.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 3.0000E+00 1.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 Note: After the first record of ID=602, the other records are all zeros. Also, I see the following for the ID=602 (second subject in the data set): Clearly there is no data in the field to be analyzed, which results in this outcome: First Order MONITORING OF SEARCH: 0ITERATION NO.: 0 OBJECTIVE VALUE: 0.00000000000000 NO. OF FUNC. EVALS.: 8 CUMULATIVE NO. OF FUNC. EVALS.: 8 PARAMETER: 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E -01 1.0000E-01 GRADIENT: 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E +00 0.0000E+00 0ITERATION NO.: 2 OBJECTIVE VALUE: 0.00000000000000 NO. OF FUNC. EVALS.: 0 CUMULATIVE NO. OF FUNC. EVALS.: 21 PARAMETER: 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E -01 1.0000E-01 GRADIENT: 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E +00 0.0000E+00 Elapsed estimation time in seconds: 0.02 At line 185 of file (unit = 10, file = 'FILE10') Fortran runtime error: End of file ERROR: nonmem failed