Tue Oct  8 20:03:49 EDT 2024
$PROBLEM    043 as 1CMT ADVAN13 with AMT in micrograms

$INPUT ROW ID NOMTIME TIME EVID CMT AMT DV FLAG STUDY
BLQ CYCLE DOSE PART PROFDAY PROFTIME WEIGHTB eff0

$DATA      xgxr12.csv IGNORE=@ IGNORE=(FLAG.NE.0) IGNORE(DOSE.LT.30)

$SUBROUTINE ADVAN13 TOL 9
$MODEL COMP=(DEPOT,DEFDOSE) COMP=(CENTRAL,DEFOBS)
;;       COMP=(PERIPH)

$PK
LTVKA=THETA(1)
LTVV2=THETA(2)
LTVCL=THETA(3)
;; LTVV3=THETA(4)
;; LTVQ=THETA(5)

MU_1=LTVKA
KA=EXP(MU_1+ETA(1))
MU_2=LTVV2
V2=EXP(MU_2+ETA(2))
MU_3=LTVCL
CL=EXP(MU_3+ETA(3))
;; MU_4=LTVV3
;; V3=EXP(MU_4+ETA(4))
;; MU_5 = LTVQ
;; Q =EXP(MU_5+ETA(5))
;; S2=V2/1000

$DES
DADT(1) = -KA*A(1)
DADT(2) = KA*A(1) - CL*A(2)/V2  ;;+ Q*(A(3)/V3-A(2)/V2)
;;DADT(3) = -Q*(A(3)/V3-A(2)/V2)


$ERROR
  IPRED=A(2)/V2
  IRES=DV-IPRED

  ;; IF (IPRED.GT.1) THEN
  ;;   W = SQRT(IPRED**2*SIGMA(1,1) + SIGMA(2,2))
  ;; ELSE
  ;;   W=1
  ;; ENDIF

  ;; IWRES=IRES/W
  Y=IPRED+IPRED*ERR(1)+ERR(2)

;-----------------------INITIAL ESTIMATES---------------------------------
$THETA  (-1)             ; LTVKA
$THETA  (9)             ; LTVV2
$THETA  (1)             ; LTVCL
;; $THETA  (5)          FIX   ; LTVV3
;; $THETA  (-1000) FIX             ; LTVQ

$OMEGA 0.1
$OMEGA 0.1
$OMEGA 0.1
;; $OMEGA 0 FIX
;; $OMEGA 0 FIX

$SIGMA 0.1
$SIGMA 0.1

$ESTIMATION METHOD=1 POSTHOC INTER MAXEVAL=9999 NSIG=2 SIGL=9
           PRINT=10 NOABORT MSFO=xgxr046.msf
;; $ESTIMATION METHOD=SAEM INTERACTION NOABORT NBURN=1000 NITER=1000 CTYPE=3 MAX=99999 NSIG=3 SEED=3442 PRINT=10 RANMETHOD=P MSFO=xgxr045.msf

;; $ESTIMATION METHOD=IMP INTERACTION EONLY=1 NITER=20 PRINT=1 ISAMPLE=5000 RANMETHOD=P
																	    
;$COV PRINT=E

$TABLE ROW LTVKA LTVV2 LTVCL KA V2 CL PRED IPRED Y NOPRINT FILE=xgxr046_res.txt
$TABLE ETAS(1:LAST) NOAPPEND NOPRINT FILE=xgxr046_etas.txt

NM-TRAN MESSAGES
  
 WARNINGS AND ERRORS (IF ANY) FOR PROBLEM    1
             
 (WARNING  2) NM-TRAN INFERS THAT THE DATA ARE POPULATION.

License Registered to: Vertex Pharmaceuticals Inc
Expiration Date:    14 JAN 2025
Current Date:        8 OCT 2024
Days until program expires : 101
1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) VERSION 7.5.0
 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
 043 as 1CMT ADVAN13 with AMT in micrograms
0DATA CHECKOUT RUN:              NO
 DATA SET LOCATED ON UNIT NO.:    2
 THIS UNIT TO BE REWOUND:        NO
 NO. OF DATA RECS IN DATA SET:      731
 NO. OF DATA ITEMS IN DATA SET:  19
 ID DATA ITEM IS DATA ITEM NO.:   2
 DEP VARIABLE IS DATA ITEM NO.:   8
 MDV DATA ITEM IS DATA ITEM NO.: 19
0INDICES PASSED TO SUBROUTINE PRED:
   5   4   7   0   0   0   6   0   0   0   0
0LABELS FOR DATA ITEMS:
 ROW ID NOMTIME TIME EVID CMT AMT DV FLAG STUDY BLQ CYCLE DOSE PART PROFDAY PROFTIME WEIGHTB eff0 MDV
0(NONBLANK) LABELS FOR PRED-DEFINED ITEMS:
 LTVKA LTVV2 LTVCL KA V2 CL IPRED Y
0FORMAT FOR DATA:
 (E4.0,E3.0,E4.0,E8.0,2E1.0,E5.0,E8.0,4E1.0,E3.0,2E1.0,3E6.0,1F2.0)

 TOT. NO. OF OBS RECS:      641
 TOT. NO. OF INDIVIDUALS:       90
0LENGTH OF THETA:   3
0DEFAULT THETA BOUNDARY TEST OMITTED:    NO
0OMEGA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:   3
0DEFAULT OMEGA BOUNDARY TEST OMITTED:    NO
0SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:   2
0DEFAULT SIGMA BOUNDARY TEST OMITTED:    NO
0INITIAL ESTIMATE OF THETA:
  -0.1000E+01  0.9000E+01  0.1000E+01
0INITIAL ESTIMATE OF OMEGA:
 0.1000E+00
 0.0000E+00   0.1000E+00
 0.0000E+00   0.0000E+00   0.1000E+00
0INITIAL ESTIMATE OF SIGMA:
 0.1000E+00
 0.0000E+00   0.1000E+00
0TABLES STEP OMITTED:    NO
 NO. OF TABLES:           2
 SEED NUMBER (SEED):    11456
 RANMETHOD:             3U
 MC SAMPLES (ESAMPLE):    300
 WRES SQUARE ROOT TYPE (WRESCHOL): EIGENVALUE
0-- TABLE   1 --
0RECORDS ONLY:    ALL
04 COLUMNS APPENDED:    YES
 PRINTED:                NO
 HEADER:                YES
 FILE TO BE FORWARDED:   NO
 FORMAT:                S1PE11.4
 IDFORMAT:
 LFORMAT:
 RFORMAT:
 FIXED_EFFECT_ETAS:
0USER-CHOSEN ITEMS:
 ROW LTVKA LTVV2 LTVCL KA V2 CL IPRED Y
0-- TABLE   2 --
0RECORDS ONLY:    ALL
04 COLUMNS APPENDED:    NO
 PRINTED:                NO
 HEADER:                YES
 FILE TO BE FORWARDED:   NO
 FORMAT:                S1PE11.4
 IDFORMAT:
 LFORMAT:
 RFORMAT:
 FIXED_EFFECT_ETAS:
0USER-CHOSEN ITEMS:
 ETA1 ETA2 ETA3
1DOUBLE PRECISION PREDPP VERSION 7.5.0

 GENERAL NONLINEAR KINETICS MODEL WITH STIFF/NONSTIFF EQUATIONS (LSODA, ADVAN13)
0MODEL SUBROUTINE USER-SUPPLIED - ID NO. 9999
0MAXIMUM NO. OF BASIC PK PARAMETERS:   3
0COMPARTMENT ATTRIBUTES
 COMPT. NO.   FUNCTION   INITIAL    ON/OFF      DOSE      DEFAULT    DEFAULT
                         STATUS     ALLOWED    ALLOWED    FOR DOSE   FOR OBS.
    1         DEPOT        ON         YES        YES        YES        NO
    2         CENTRAL      ON         YES        YES        NO         YES
    3         OUTPUT       OFF        YES        NO         NO         NO
 INITIAL (BASE) TOLERANCE SETTINGS:
 NRD (RELATIVE) VALUE(S) OF TOLERANCE:   9
 ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE:  12
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            *           *           *           *           *
    3            *           -           -           -           -
             - PARAMETER IS NOT ALLOWED FOR THIS MODEL
             * PARAMETER IS NOT SUPPLIED BY PK SUBROUTINE;
               WILL DEFAULT TO ONE IF APPLICABLE
0DATA ITEM INDICES USED BY PRED ARE:
   EVENT ID DATA ITEM IS DATA ITEM NO.:      5
   TIME DATA ITEM IS DATA ITEM NO.:          4
   DOSE AMOUNT DATA ITEM IS DATA ITEM NO.:   7
   COMPT. NO. DATA ITEM IS DATA ITEM NO.:    6

0PK SUBROUTINE CALLED WITH EVERY EVENT RECORD.
 PK SUBROUTINE NOT CALLED AT NONEVENT (ADDITIONAL OR LAGGED) DOSE TIMES.
0ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD.
0ERROR SUBROUTINE INDICATES THAT DERIVATIVES OF COMPARTMENT AMOUNTS ARE USED.
0DES SUBROUTINE USES COMPACT STORAGE MODE.
1


 #TBLN:      1
 #METH: First Order Conditional Estimation with Interaction

 ESTIMATION STEP OMITTED:                 NO
 ANALYSIS TYPE:                           POPULATION
 NUMBER OF SADDLE POINT RESET ITERATIONS:      0
 GRADIENT METHOD USED:               NOSLOW
 CONDITIONAL ESTIMATES USED:              YES
 CENTERED ETA:                            NO
 EPS-ETA INTERACTION:                     YES
 LAPLACIAN OBJ. FUNC.:                    NO
 NO. OF FUNCT. EVALS. ALLOWED:            9999
 NO. OF SIG. FIGURES REQUIRED:            2
 INTERMEDIATE PRINTOUT:                   YES
 ESTIMATE OUTPUT TO MSF:                  YES
 ABORT WITH PRED EXIT CODE 1:             NO
 IND. OBJ. FUNC. VALUES SORTED:           NO
 NUMERICAL DERIVATIVE
       FILE REQUEST (NUMDER):               NONE
 MAP (ETAHAT) ESTIMATION METHOD (OPTMAP):   0
 ETA HESSIAN EVALUATION METHOD (ETADER):    0
 INITIAL ETA FOR MAP ESTIMATION (MCETA):    0
 SIGDIGITS FOR MAP ESTIMATION (SIGLO):      9
 GRADIENT SIGDIGITS OF
       FIXED EFFECTS PARAMETERS (SIGL):     9
 NOPRIOR SETTING (NOPRIOR):                 0
 NOCOV SETTING (NOCOV):                     OFF
 DERCONT SETTING (DERCONT):                 OFF
 FINAL ETA RE-EVALUATION (FNLETA):          1
 EXCLUDE NON-INFLUENTIAL (NON-INFL.) ETAS
       IN SHRINKAGE (ETASTYPE):             NO
 NON-INFL. ETA CORRECTION (NONINFETA):      0
 RAW OUTPUT FILE (FILE): xgxr046.ext
 EXCLUDE TITLE (NOTITLE):                   NO
 EXCLUDE COLUMN LABELS (NOLABEL):           NO
 FORMAT FOR ADDITIONAL FILES (FORMAT):      S1PE12.5
 PARAMETER ORDER FOR OUTPUTS (ORDER):       TSOL
 KNUTHSUMOFF:                               0
 INCLUDE LNTWOPI:                           NO
 INCLUDE CONSTANT TERM TO PRIOR (PRIORC):   NO
 INCLUDE CONSTANT TERM TO OMEGA (ETA) (OLNTWOPI):NO
 ADDITIONAL CONVERGENCE TEST (CTYPE=4)?:    NO
 EM OR BAYESIAN METHOD USED:                 NONE

 TOLERANCES FOR ESTIMATION/EVALUATION STEP:
 NRD (RELATIVE) VALUE(S) OF TOLERANCE:   9
 ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE:  12
 TOLERANCES FOR COVARIANCE STEP:
 NRD (RELATIVE) VALUE(S) OF TOLERANCE:   9
 ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE:  12
 TOLERANCES FOR TABLE/SCATTER STEP:
 NRD (RELATIVE) VALUE(S) OF TOLERANCE:   9
 ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE:  12

 THE FOLLOWING LABELS ARE EQUIVALENT
 PRED=PREDI
 RES=RESI
 WRES=WRESI
 IWRS=IWRESI
 IPRD=IPREDI
 IRS=IRESI

 MONITORING OF SEARCH:


0ITERATION NO.:    0    OBJECTIVE VALUE:   3778.61330193561        NO. OF FUNC. EVALS.:   7
 CUMULATIVE NO. OF FUNC. EVALS.:        7
 NPARAMETR: -1.0000E+00  9.0000E+00  1.0000E+00  1.0000E-01  1.0000E-01  1.0000E-01  1.0000E-01  1.0000E-01
 PARAMETER: -1.0000E-01  1.0000E-01  1.0000E-01  1.0000E-01  1.0000E-01  1.0000E-01  1.0000E-01  1.0000E-01
 GRADIENT:   6.4724E+03 -1.4399E+05 -1.2581E+01 -2.1411E+02 -1.4486E+03 -5.9039E-04 -4.1402E+03 -2.2285E+02

0ITERATION NO.:   10    OBJECTIVE VALUE:  -988.341256925904        NO. OF FUNC. EVALS.:  92
 CUMULATIVE NO. OF FUNC. EVALS.:       99
 NPARAMETR:  1.8464E+00  1.2085E+01  9.9386E+00  3.9936E-01  1.8100E-01  5.2918E-02  5.5141E-01  1.0396E-02
 PARAMETER:  1.8464E-01  1.3428E-01  9.9386E-01  7.9234E-01  3.9665E-01 -2.1821E-01  9.5365E-01 -1.0319E+00
 GRADIENT:   5.5814E+02  1.3287E+04 -6.0286E+02  2.7067E+01  1.1528E+01 -9.1799E+00  3.4057E+02  1.8573E+02

0ITERATION NO.:   20    OBJECTIVE VALUE:  -1414.32235028665        NO. OF FUNC. EVALS.:  83
 CUMULATIVE NO. OF FUNC. EVALS.:      182
 NPARAMETR:  1.1045E+00  1.1476E+01  9.8238E+00  3.3707E-02  1.3792E-01  1.5735E-01  9.0850E-02  2.8174E-03
 PARAMETER:  1.1045E-01  1.2752E-01  9.8238E-01 -4.4373E-01  2.6075E-01  3.2664E-01  5.2018E-02 -1.6847E+00
 GRADIENT:  -6.3277E+01  1.3069E+03 -5.0593E+01  2.9791E+00  2.4356E-01 -5.6502E+00 -1.0366E+00  1.6800E+00

0ITERATION NO.:   27    OBJECTIVE VALUE:  -1414.98814398363        NO. OF FUNC. EVALS.:  63
 CUMULATIVE NO. OF FUNC. EVALS.:      245
 NPARAMETR:  1.1198E+00  1.1465E+01  9.8312E+00  1.5324E-02  1.3770E-01  1.6566E-01  9.1529E-02  2.7866E-03
 PARAMETER:  1.1198E-01  1.2739E-01  9.8312E-01 -8.3787E-01  2.5994E-01  3.5238E-01  5.5743E-02 -1.6902E+00
 GRADIENT:  -5.3946E-01 -1.0272E+02 -1.5778E+00 -9.3071E-03 -8.9149E-02 -3.2266E-01 -4.0596E-01 -2.3906E-01

 #TERM:
0MINIMIZATION SUCCESSFUL
 NO. OF FUNCTION EVALUATIONS USED:      245
 NO. OF SIG. DIGITS IN FINAL EST.:  2.2

 ETABAR IS THE ARITHMETIC MEAN OF THE ETA-ESTIMATES,
 AND THE P-VALUE IS GIVEN FOR THE NULL HYPOTHESIS THAT THE TRUE MEAN IS 0.

 ETABAR:        -6.4101E-04 -1.1825E-02 -3.0324E-04
 SE:             3.1218E-03  3.4607E-02  3.6861E-02
 N:                      90          90          90

 P VAL.:         8.3731E-01  7.3257E-01  9.9344E-01

 ETASHRINKSD(%)  7.5941E+01  1.1029E+01  1.3601E+01
 ETASHRINKVR(%)  9.4212E+01  2.0842E+01  2.5352E+01
 EBVSHRINKSD(%)  7.5912E+01  1.0829E+01  1.4031E+01
 EBVSHRINKVR(%)  9.4198E+01  2.0486E+01  2.6093E+01
 RELATIVEINF(%)  5.1565E+00  7.0665E+01  7.3906E+01
 EPSSHRINKSD(%)  1.0920E+01  1.0920E+01
 EPSSHRINKVR(%)  2.0648E+01  2.0648E+01

  
 TOTAL DATA POINTS NORMALLY DISTRIBUTED (N):          641
 N*LOG(2PI) CONSTANT TO OBJECTIVE FUNCTION:    1178.0791995683903     
 OBJECTIVE FUNCTION VALUE WITHOUT CONSTANT:   -1414.9881439836311     
 OBJECTIVE FUNCTION VALUE WITH CONSTANT:      -236.90894441524074     
 REPORTED OBJECTIVE FUNCTION DOES NOT CONTAIN CONSTANT
  
 TOTAL EFFECTIVE ETAS (NIND*NETA):                           270
  
 #TERE:
 Elapsed estimation  time in seconds:    62.73
 Elapsed postprocess time in seconds:     0.56
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION              ********************
 #OBJT:**************                       MINIMUM VALUE OF OBJECTIVE FUNCTION                      ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 





 #OBJV:********************************************    -1414.988       **************************************************
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION              ********************
 ********************                             FINAL PARAMETER ESTIMATE                           ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 


 THETA - VECTOR OF FIXED EFFECTS PARAMETERS   *********


         TH 1      TH 2      TH 3     
 
         1.12E+00  1.15E+01  9.83E+00
 


 OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS  ********


         ETA1      ETA2      ETA3     
 
 ETA1
+        1.53E-02
 
 ETA2
+        0.00E+00  1.38E-01
 
 ETA3
+        0.00E+00  0.00E+00  1.66E-01
 


 SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS  ****


         EPS1      EPS2     
 
 EPS1
+        9.15E-02
 
 EPS2
+        0.00E+00  2.79E-03
 
1


 OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS  *******


         ETA1      ETA2      ETA3     
 
 ETA1
+        1.24E-01
 
 ETA2
+        0.00E+00  3.71E-01
 
 ETA3
+        0.00E+00  0.00E+00  4.07E-01
 


 SIGMA - CORR MATRIX FOR RANDOM EFFECTS - EPSILONS  ***


         EPS1      EPS2     
 
 EPS1
+        3.03E-01
 
 EPS2
+        0.00E+00  5.28E-02
 
 Elapsed finaloutput time in seconds:     0.03
1THERE ARE ERROR MESSAGES IN FILE PRDERR                                                                  
 #CPUT: Total CPU Time in Seconds,       63.443
Stop Time:
Tue Oct  8 20:04:57 EDT 2024
