Fri Sep  8 01:33:49 PM EDT 2023
$PROBLEM    PK

;@ Variables 17/20 @;
$INPUT ROW ID NOMTIME TIME EVID CMT AMT DV FLAG STUDY
BLQ CYCLE DOSE PART PROFDAY PROFTIME WEIGHTB eff0

$DATA     ../data/xgxr1.csv IGNORE=@ IGNORE=(FLAG.NE.0)

$SUBROUTINE ADVAN4 TRANS4

$PK
TVKA=THETA(1)
TVV2=THETA(2)
TVCL=THETA(3)
TVV3=THETA(4)
TVQ=THETA(5)
                   
KA=TVKA*EXP(ETA(1))
V2=TVV2*EXP(ETA(2))
CL=TVCL*EXP(ETA(3))
V3=TVV3*EXP(ETA(4))
Q=TVQ*EXP(ETA(5))

$ERROR
  IPRED=F
  IRES=DV-IPRED

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

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

;-----------------------INITIAL ESTIMATES---------------------------------
$THETA  (0,0.9)           ; POPKA
$THETA  (0,4.2)             ; POPCL
$THETA  (0,3.6)             ; POPV2
$THETA  (0,5.81)             ; POPV3
$THETA  (0,3.44)           ; POPQ 

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

$SIGMA .2
$SIGMA .2

$ESTIMATION METHOD=1 POSTHOC INTER MAXEVAL=9999 NSIG=2 SIGL=9
            PRINT=10 NOABORT


$TABLE ROW   TVKA   TVV2     TVCL  TVV3  TVQ  KA  V2  CL  V3  Q
       PRED  IPRED  NOPRINT  FILE=xgxr001_res.txt

NM-TRAN MESSAGES
  
 WARNINGS AND ERRORS (IF ANY) FOR PROBLEM    1
             
 (WARNING  2) NM-TRAN INFERS THAT THE DATA ARE POPULATION.
             
 (WARNING  23) $PK DOES NOT DEFINE A SCALE PARAMETER FOR THE CENTRAL
 COMPARTMENT.  WITH THIS TRANS, IT MAY NOT BE POSSIBLE TO SEPARATELY
 OBTAIN ESTIMATES OF PARAMETERS AFFECTING CLEARANCE AND VOLUME.
             
 (WARNING  79) SIGMA IS USED ON THE RIGHT. WITH A SUBSEQUENT RUN, IF AN
 INITIAL ESTIMATE OF A DIAGONAL BLOCK OF SIGMA IS TO BE COMPUTED BY
 NONMEM, THAT BLOCK WILL BE SET TO AN IDENTITY MATRIX DURING THAT
 COMPUTATION. THIS COULD LEAD TO AN ARITHMETIC EXCEPTION.*

 * THE MAXIMUM NUMBER OF WARNINGS OF ONE OR MORE TYPES WAS REACHED.
 IT IS POSSIBLE THAT SOME WARNING MESSAGES WERE SUPPRESSED.
  
Note: Analytical 2nd Derivatives are constructed in FSUBS but are never used.
      You may insert $ABBR DERIV2=NO after the first $PROB to save FSUBS construction and compilation time
  

License Registered to: Philip Harder Delff for developing R packages that Interact with NONMEM
Expiration Date:    14 SEP 2024
Current Date:        8 SEP 2023
Days until program expires : 371
1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) VERSION 7.5.1
 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
 PK
0DATA CHECKOUT RUN:              NO
 DATA SET LOCATED ON UNIT NO.:    2
 THIS UNIT TO BE REWOUND:        NO
 NO. OF DATA RECS IN DATA SET:      905
 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:
 TVKA TVV2 TVCL TVV3 TVQ KA V2 CL V3 Q IPRED
0FORMAT FOR DATA:
 (2(8E9.0/),2E9.0,1F2.0)

 TOT. NO. OF OBS RECS:      755
 TOT. NO. OF INDIVIDUALS:      150
0LENGTH OF THETA:   5
0DEFAULT THETA BOUNDARY TEST OMITTED:    NO
0OMEGA HAS BLOCK FORM:
  1
  0  2
  0  0  3
  0  0  0  4
  0  0  0  0  5
0DEFAULT OMEGA BOUNDARY TEST OMITTED:    NO
0SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:   2
0DEFAULT SIGMA BOUNDARY TEST OMITTED:    NO
0INITIAL ESTIMATE OF THETA:
 LOWER BOUND    INITIAL EST    UPPER BOUND
  0.0000E+00     0.9000E+00     0.1000E+07
  0.0000E+00     0.4200E+01     0.1000E+07
  0.0000E+00     0.3600E+01     0.1000E+07
  0.0000E+00     0.5810E+01     0.1000E+07
  0.0000E+00     0.3440E+01     0.1000E+07
0INITIAL ESTIMATE OF OMEGA:
 BLOCK SET NO.   BLOCK                                                                    FIXED
        1                                                                                   NO
                  0.1000E+00
        2                                                                                   NO
                  0.1000E+00
        3                                                                                   NO
                  0.1000E+00
        4                                                                                  YES
                  0.0000E+00
        5                                                                                  YES
                  0.0000E+00
0INITIAL ESTIMATE OF SIGMA:
 0.2000E+00
 0.0000E+00   0.2000E+00
0TABLES STEP OMITTED:    NO
 NO. OF TABLES:           1
 SEED NUMBER (SEED):    11456
 NPDTYPE:    0
 INTERPTYPE:    0
 RANMETHOD:             3U
 MC SAMPLES (ESAMPLE):    300
 WRES SQUARE ROOT TYPE (WRESCHOL): EIGENVALUE
0-- TABLE   1 --
0RECORDS ONLY:    ALL
04 COLUMNS APPENDED:    YES
 PRINTED:                NO
 HEADERS:               YES
 FILE TO BE FORWARDED:   NO
 FORMAT:                S1PE11.4
 IDFORMAT:
 LFORMAT:
 RFORMAT:
 FIXED_EFFECT_ETAS:
0USER-CHOSEN ITEMS:
 ROW TVKA TVV2 TVCL TVV3 TVQ KA V2 CL V3 Q IPRED
1DOUBLE PRECISION PREDPP VERSION 7.5.1

 TWO COMPARTMENT MODEL WITH FIRST-ORDER ABSORPTION (ADVAN4)
0MAXIMUM NO. OF BASIC PK PARAMETERS:   5
0BASIC PK PARAMETERS (AFTER TRANSLATION):
   BASIC PK PARAMETER NO.  1: ELIMINATION RATE (K)
   BASIC PK PARAMETER NO.  2: CENTRAL-TO-PERIPH. RATE (K23)
   BASIC PK PARAMETER NO.  3: PERIPH.-TO-CENTRAL RATE (K32)
   BASIC PK PARAMETER NO.  5: ABSORPTION RATE (KA)
 TRANSLATOR WILL CONVERT PARAMETERS
 CL, V2, Q, V3 TO K, K23, K32 (TRANS4)
0COMPARTMENT ATTRIBUTES
 COMPT. NO.   FUNCTION   INITIAL    ON/OFF      DOSE      DEFAULT    DEFAULT
                         STATUS     ALLOWED    ALLOWED    FOR DOSE   FOR OBS.
    1         DEPOT        OFF        YES        YES        YES        NO
    2         CENTRAL      ON         NO         YES        NO         YES
    3         PERIPH.      ON         NO         YES        NO         NO
    4         OUTPUT       OFF        YES        NO         NO         NO
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            *           *           *           *           *
    4            *           -           -           -           -
             - 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.
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:                  NO
 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): xgxr001.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


 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:   3516.44311416803        NO. OF FUNC. EVALS.:   9
 CUMULATIVE NO. OF FUNC. EVALS.:        9
 NPARAMETR:  9.0000E-01  4.2000E+00  3.6000E+00  5.8100E+00  3.4400E+00  1.0000E-01  1.0000E-01  1.0000E-01  2.0000E-01  2.0000E-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  1.0000E-01  1.0000E-01

 GRADIENT:   2.8583E+02  1.6750E+03 -1.5241E+03 -1.4331E+02 -7.5533E+00  1.4192E+00 -1.0946E+03 -9.6534E+02 -2.1379E+03  6.5453E+01


0ITERATION NO.:   10    OBJECTIVE VALUE:  -1627.97009848195        NO. OF FUNC. EVALS.: 105
 CUMULATIVE NO. OF FUNC. EVALS.:      114
 NPARAMETR:  1.5543E-01  2.6679E-01  6.7175E+00  1.3487E+00  9.9272E+01  4.1057E-02  9.1778E-02  7.8655E-01  3.0937E-01  2.6088E-03

 PARAMETER: -1.6562E+00 -2.6564E+00  7.2378E-01 -1.3604E+00  3.4624E+00 -3.4511E-01  5.7103E-02  1.1312E+00  3.1811E-01 -2.0697E+00

 GRADIENT:  -9.1901E+01 -1.2417E+02  8.0114E+01  4.7596E+01 -3.2233E+00 -6.5653E+01  1.1877E+01  1.4543E+02  3.2070E+02  1.0443E+02


0ITERATION NO.:   20    OBJECTIVE VALUE:  -1948.47061584784        NO. OF FUNC. EVALS.: 105
 CUMULATIVE NO. OF FUNC. EVALS.:      219
 NPARAMETR:  1.7825E-01  4.2000E-02  7.0171E-01  1.7233E-01  5.5408E+02  1.8554E-01  8.1252E-02  3.4031E-02  1.1199E-01  1.2937E-03

 PARAMETER: -1.5192E+00 -4.6627E+00 -1.5352E+00 -3.4179E+00  5.1818E+00  4.0905E-01 -3.8081E-03 -4.3894E-01 -1.8996E-01 -2.4204E+00

 GRADIENT:   1.6037E+01  0.0000E+00 -2.9104E+01  2.3884E+00 -3.7901E-02 -2.0895E+00 -4.6448E+00  5.5434E+00  1.2662E+01 -1.1312E+00


0ITERATION NO.:   30    OBJECTIVE VALUE:  -1951.53590766537        NO. OF FUNC. EVALS.: 101
 CUMULATIVE NO. OF FUNC. EVALS.:      320
 NPARAMETR:  1.8139E-01  4.2000E-02  7.2468E-01  1.7858E-01  8.4141E+03  2.1068E-01  1.2177E-01  2.3585E-04  1.0585E-01  1.3961E-03

 PARAMETER: -1.5017E+00 -4.5062E+00 -1.5030E+00 -3.3823E+00  7.9022E+00  4.7259E-01  1.9850E-01 -2.9249E+00 -2.1815E-01 -2.3823E+00

 GRADIENT:   5.8752E-01  0.0000E+00 -2.6290E-01 -1.8279E-01 -4.4591E-03  2.2842E-01  2.2496E-01  1.5960E-02  1.5529E-01  1.7802E-01


0ITERATION NO.:   37    OBJECTIVE VALUE:  -1951.53785634257        NO. OF FUNC. EVALS.: 134
 CUMULATIVE NO. OF FUNC. EVALS.:      454
 NPARAMETR:  1.8123E-01  4.2000E-02  7.2481E-01  1.7864E-01  1.0732E+04  2.1013E-01  1.2148E-01  2.1637E-04  1.0595E-01  1.3951E-03

 PARAMETER: -1.5026E+00 -4.5142E+00 -1.5028E+00 -3.3820E+00  8.1455E+00  4.7128E-01  1.9727E-01 -2.9680E+00 -2.1769E-01 -2.3827E+00

 GRADIENT:  -2.6234E-01  0.0000E+00 -2.3642E-01  1.3309E-01 -3.4624E-03 -1.1673E-02 -2.9772E-02  1.4095E-02  2.9457E-01  1.4536E-01


 #TERM:
0MINIMIZATION SUCCESSFUL
 NO. OF FUNCTION EVALUATIONS USED:      454
 NO. OF SIG. DIGITS IN FINAL EST.:  2.1
0PARAMETER ESTIMATE IS NEAR ITS BOUNDARY
 THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED

 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:         1.0063E-02  6.9481E-03 -1.5906E-05  0.0000E+00  0.0000E+00
 SE:             3.2599E-02  2.3965E-02  4.7284E-05  0.0000E+00  0.0000E+00
 N:                     131         131         131         131         131

 P VAL.:         7.5754E-01  7.7188E-01  7.3657E-01  1.0000E+00  1.0000E+00

 ETASHRINKSD(%)  1.8606E+01  2.1300E+01  9.6321E+01  0.0000E+00  0.0000E+00
 ETASHRINKVR(%)  3.3750E+01  3.8063E+01  9.9865E+01  0.0000E+00  0.0000E+00
 EBVSHRINKSD(%)  1.9011E+01  2.1435E+01  9.6243E+01  0.0000E+00  0.0000E+00
 EBVSHRINKVR(%)  3.4409E+01  3.8276E+01  9.9859E+01  0.0000E+00  0.0000E+00
 RELATIVEINF(%)  5.6894E+01  1.5090E+01  3.6830E-02  0.0000E+00  0.0000E+00
 EPSSHRINKSD(%)  1.0792E+01  1.0792E+01
 EPSSHRINKVR(%)  2.0419E+01  2.0419E+01

  
 TOTAL DATA POINTS NORMALLY DISTRIBUTED (N):          755
 N*LOG(2PI) CONSTANT TO OBJECTIVE FUNCTION:    1387.5971851390557     
 OBJECTIVE FUNCTION VALUE WITHOUT CONSTANT:   -1951.5378563425709     
 OBJECTIVE FUNCTION VALUE WITH CONSTANT:      -563.94067120351519     
 REPORTED OBJECTIVE FUNCTION DOES NOT CONTAIN CONSTANT
  
 TOTAL EFFECTIVE ETAS (NIND*NETA):                           393
  
 #TERE:
 Elapsed estimation  time in seconds:     3.79
 Elapsed postprocess time in seconds:     0.05
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION              ********************
 #OBJT:**************                       MINIMUM VALUE OF OBJECTIVE FUNCTION                      ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 





 #OBJV:********************************************    -1951.538       **************************************************
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION              ********************
 ********************                             FINAL PARAMETER ESTIMATE                           ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 


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


         TH 1      TH 2      TH 3      TH 4      TH 5     
 
         1.81E-01  4.20E-02  7.25E-01  1.79E-01  1.07E+04
 


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


         ETA1      ETA2      ETA3      ETA4      ETA5     
 
 ETA1
+        2.10E-01
 
 ETA2
+        0.00E+00  1.21E-01
 
 ETA3
+        0.00E+00  0.00E+00  2.16E-04
 
 ETA4
+        0.00E+00  0.00E+00  0.00E+00  0.00E+00
 
 ETA5
+        0.00E+00  0.00E+00  0.00E+00  0.00E+00  0.00E+00
 


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


         EPS1      EPS2     
 
 EPS1
+        1.06E-01
 
 EPS2
+        0.00E+00  1.40E-03
 
1


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


         ETA1      ETA2      ETA3      ETA4      ETA5     
 
 ETA1
+        4.58E-01
 
 ETA2
+        0.00E+00  3.49E-01
 
 ETA3
+        0.00E+00  0.00E+00  1.47E-02
 
 ETA4
+        0.00E+00  0.00E+00  0.00E+00  0.00E+00
 
 ETA5
+        0.00E+00  0.00E+00  0.00E+00  0.00E+00  0.00E+00
 


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


         EPS1      EPS2     
 
 EPS1
+        3.25E-01
 
 EPS2
+        0.00E+00  3.74E-02
 
 Elapsed finaloutput time in seconds:     0.02
 #CPUT: Total CPU Time in Seconds,        3.962
Stop Time:
Fri Sep  8 01:33:56 PM EDT 2023
