Thu Jul 28 16:47:58 PDT 2011 $PROBLEM Tremblay model with MTIME, MPAST $INPUT ID AMT=DROP TIME CP=DV WT $DATA THEOPP RECS=12 $SUBROUTINE ADVAN6 TOL=6 $MODEL NCOMP=1 COMP=(CENTRAL) $PK CV=THETA(1)*EXP(ETA(1)) CV2=CV**2 MDT=THETA(2)*EXP(ETA(2)) K=THETA(3)*EXP(ETA(3)) V=THETA(4)*EXP(ETA(4)) MTIME(1)=THETA(5)+ETA(5) DOSE=1000000 $DES P1=2*3.141593*CV2*(T+0.00001)**3 P2=((T+0.00001)-MDT)**2 P3=2*CV2*MDT*(T+0.00001) P4=SQRT(MDT/P1) RATIO=-1*(P2/P3) P5=EXP(RATIO) IG=P4*P5 INPUT=IG*MPAST(1) DADT(1)=(DOSE/V)*INPUT-K*A(1) $ERROR A1=A(1) Y=F+ERR(1) $THETA 1 1 1 1 1 $OMEGA 1 1 1 1 1 $SIGMA 1 $TABLE TIME INPUT A1 NM-TRAN MESSAGES WARNINGS AND ERRORS (IF ANY) FOR PROBLEM 1 (WARNING 2) NM-TRAN INFERS THAT THE DATA ARE POPULATION. (WARNING 80) $PK SETS MTIME BUT NOT MTDIFF. WHEN AN ELEMENT OF MTIME IS RESET, THEN $PK SHOULD ALSO SET MTDIFF=1. (DATA WARNING 4) RECORD 1, DATA ITEM 3, CONTENTS: THE DV DATA ITEM IS NULL, BUT THE MDV DATA ITEM IS 0 AND NO $SIMULATION RECORD IS PRESENT. (WARNING 48) DES-DEFINED ITEMS ARE COMPUTED ONLY WHEN EVENT TIME INCREASES. E.G., DISPLAYED VALUES ASSOCIATED WITH THE FIRST EVENT RECORD OF AN INDIVIDUAL RECORD ARE COMPUTED WITH (THE LAST ADVANCE TO) AN EVENT TIME OF THE PRIOR INDIVIDUAL RECORD. CREATING MUMODEL ROUTINE... License Registered to: Temporary License File for Installation Expiration Date: 31 JUL 2011 Current Date: 28 JUL 2011 **** WARNING!!! Days until program expires : 3 **** **** CONTACT idssoftware@iconplc.com FOR RENEWAL **** 1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) VERSION 7.2.0 ORIGINALLY DEVELOPED BY STUART BEAL, LEWIS SHEINER, AND ALISON BOECKMANN CURRENT DEVELOPERS ARE ROBERT BAUER, ICON DEVELOPMENT SOLUTIONS, AND ALISON BOECKMANN. IMPLEMENTATION, EFFICIENCY, AND STANDARDIZATION PERFORMED BY NOUS INFOSYSTEMS. PROBLEM NO.: 1 Tremblay model with MTIME, MPAST 0DATA CHECKOUT RUN: NO DATA SET LOCATED ON UNIT NO.: 2 THIS UNIT TO BE REWOUND: NO NO. OF DATA RECS IN DATA SET: 12 NO. OF DATA ITEMS IN DATA SET: 6 ID DATA ITEM IS DATA ITEM NO.: 1 DEP VARIABLE IS DATA ITEM NO.: 3 MDV DATA ITEM IS DATA ITEM NO.: 6 0INDICES PASSED TO SUBROUTINE PRED: 5 2 0 0 0 0 0 0 0 0 0 0LABELS FOR DATA ITEMS: ID TIME CP WT EVID MDV 0(NONBLANK) LABELS FOR PRED-DEFINED ITEMS: INPUT A1 0FORMAT FOR DATA: (4E6.0,2F2.0) TOT. NO. OF OBS RECS: 12 TOT. NO. OF INDIVIDUALS: 1 0LENGTH OF THETA: 5 0DEFAULT THETA BOUNDARY TEST OMITTED: NO 0OMEGA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 5 0DEFAULT OMEGA BOUNDARY TEST OMITTED: NO 0SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 1 0DEFAULT SIGMA BOUNDARY TEST OMITTED: NO 0INITIAL ESTIMATE OF THETA: 0.1000E+01 0.1000E+01 0.1000E+01 0.1000E+01 0.1000E+01 0INITIAL ESTIMATE OF OMEGA: 0.1000E+01 0.0000E+00 0.1000E+01 0.0000E+00 0.0000E+00 0.1000E+01 0.0000E+00 0.0000E+00 0.0000E+00 0.1000E+01 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.1000E+01 0INITIAL ESTIMATE OF SIGMA: 0.1000E+01 0TABLES STEP OMITTED: NO NO. OF TABLES: 1 0-- TABLE 1 -- PRINTED: YES 0USER-CHOSEN ITEMS: TIME INPUT A1 THE FOLLOWING LABELS ARE EQUIVALENT PRED=NPRED RES=NRES WRES=NWRES 1DOUBLE PRECISION PREDPP VERSION 7.2.0 GENERAL NONLINEAR KINETICS MODEL (ADVAN6) 0MODEL SUBROUTINE USER-SUPPLIED - ID NO. 9999 0MAXIMUM NO. OF BASIC PK PARAMETERS: 5 0COMPARTMENT ATTRIBUTES COMPT. NO. FUNCTION INITIAL ON/OFF DOSE DEFAULT DEFAULT STATUS ALLOWED ALLOWED FOR DOSE FOR OBS. 1 CENTRAL ON YES YES YES YES 2 OUTPUT OFF YES NO NO NO 0NRD VALUE FROM SUBROUTINE TOL: 6 1 ADDITIONAL PK PARAMETERS - ASSIGNMENT OF ROWS IN GG COMPT. NO. INDICES SCALE BIOAVAIL. ZERO-ORDER ZERO-ORDER ABSORB FRACTION RATE DURATION LAG 1 * * * * * 2 * - - - - - PARAMETER IS NOT ALLOWED FOR THIS MODEL * PARAMETER IS NOT SUPPLIED BY PK SUBROUTINE; WILL DEFAULT TO ONE IF APPLICABLE 0FIRST MODEL TIME PARAMETER ASSIGNED TO ROW NO.: 6 LAST MODEL TIME PARAMETER ASSIGNED TO ROW NO.: 6 0DATA ITEM INDICES USED BY PRED ARE: EVENT ID DATA ITEM IS DATA ITEM NO.: 5 TIME DATA ITEM IS DATA ITEM NO.: 2 0PK SUBROUTINE CALLED WITH EVERY EVENT RECORD. PK SUBROUTINE CALLED AT NONEVENT (ADDITIONAL AND LAGGED) DOSE TIMES AND AT MODEL TIMES. 0ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD. 0DES SUBROUTINE USES COMPACT STORAGE MODE. 1 #TBLN: 1 #METH: First Order (Evaluation) 1 ************************************************************************************************************************ ******************** ******************** ******************** FIRST ORDER (EVALUATION) ******************** #OBJT:************** MINIMUM VALUE OF OBJECTIVE FUNCTION ******************** ******************** ******************** ************************************************************************************************************************ #OBJV:******************************************** 183.477 ************************************************** 1 ************************************************************************************************************************ ******************** ******************** ******************** FIRST ORDER (EVALUATION) ******************** ******************** FINAL PARAMETER ESTIMATE ******************** ******************** ******************** ************************************************************************************************************************ THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* TH 1 TH 2 TH 3 TH 4 TH 5 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** ETA1 ETA2 ETA3 ETA4 ETA5 ETA1 + 1.00E+00 ETA2 + 0.00E+00 1.00E+00 ETA3 + 0.00E+00 0.00E+00 1.00E+00 ETA4 + 0.00E+00 0.00E+00 0.00E+00 1.00E+00 ETA5 + 0.00E+00 0.00E+00 0.00E+00 0.00E+00 1.00E+00 SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS **** EPS1 EPS1 + 1.00E+00 1 OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS ******* ETA1 ETA2 ETA3 ETA4 ETA5 ETA1 + 1.00E+00 ETA2 + 0.00E+00 1.00E+00 ETA3 + 0.00E+00 0.00E+00 1.00E+00 ETA4 + 0.00E+00 0.00E+00 0.00E+00 1.00E+00 ETA5 + 0.00E+00 0.00E+00 0.00E+00 0.00E+00 1.00E+00 SIGMA - CORR MATRIX FOR RANDOM EFFECTS - EPSILONS *** EPS1 EPS1 + 1.00E+00 1 ************************************************************************************************************************ ******************** ******************** ******************** FIRST ORDER (EVALUATION) ******************** ******************** TABLES OF DATA AND PREDICTIONS ******************** ******************** ******************** ************************************************************************************************************************ 1TABLE NO. 1 LINE NO.TIME INPUT A1 CP PRED RES WRES 1 + 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 2 + 0.00E+00 0.00E+00 0.00E+00 7.40E-01 0.00E+00 7.40E-01 7.40E-01 3 + 2.50E-01 0.00E+00 0.00E+00 2.84E+00 0.00E+00 2.84E+00 2.84E+00 4 + 5.70E-01 0.00E+00 0.00E+00 6.57E+00 0.00E+00 6.57E+00 6.57E+00 5 + 1.12E+00 3.34E-01 4.13E+04 1.05E+01 4.13E+04 -4.12E+04 9.46E-02 6 + 2.02E+00 1.07E-01 1.23E+05 9.66E+00 1.23E+05 -1.23E+05 -6.66E-01 7 + 3.82E+00 1.89E-02 5.21E+04 8.58E+00 5.21E+04 -5.21E+04 9.65E-02 8 + 5.10E+00 6.67E-03 2.20E+04 8.36E+00 2.20E+04 -2.20E+04 2.28E-01 9 + 7.03E+00 1.61E-03 5.60E+03 7.47E+00 5.60E+03 -5.60E+03 -1.81E+00 10 + 9.05E+00 4.08E-04 1.35E+03 6.89E+00 1.35E+03 -1.34E+03 8.78E-01 11 + 1.21E+01 5.76E-05 1.68E+02 5.94E+00 1.68E+02 -1.62E+02 4.09E+00 12 + 2.44E+01 4.51E-08 1.04E-01 3.28E+00 1.04E-01 3.18E+00 3.28E+00 Stop Time: Thu Jul 28 16:48:06 PDT 2011