17-08-20
15:40
;; Description:
;; Author: user
$PROBLEM HCQ 1CMT ORAL PK MODEL (BASED ON CARMICHAEL ET AL (2003))
; ------------dataset------------
$INPUT ID SEX WT AGE TIME AMT ADDL II CMT DV MDV EVID
$DATA HCQdata5.csv IGNORE=@

; ------------model------------
$SUBROUTINE ADVAN2 TRANS2
$PK

TVCL=THETA(1)*((WT/80)**THETA(5));*((AGE/57)**THETA(5));
TVV=THETA(2)
TVKA=THETA(3)
TVF1=THETA(4)
; TVALAG1=THETA(4)


CL=TVCL*EXP(ETA(1))
V=TVV*EXP(ETA(2))
KA=TVKA;*EXP(ETA(3))
F1=TVF1;*EXP(ETA(4))
; ALAG1=TVALAG1;*EXP(ETA(3))


; scaling factor
KE=CL/V
S2=V/1000 ; dose [mg] and conc. [ng/mL]


$ERROR
Y=F*(1+EPS(1));+EPS(2)
W=F

IPRED=F ; prediction individuelle
IRES=DV-IPRED ; (individual-specific residual)
IWRES=IRES/W ; (individual-specific weighted residual)



$THETA (0,14.9207) ; CL
$THETA (0,861.385) ; V
$THETA (0,9.3023,10) ; KA
$THETA (0,0.746) FIX ; F1
;$THETA (0,0.00445) ; ALAG1
$THETA 1.20407 ; WTonCL
$OMEGA 0.163126 ; IIVCL
0.27101 ; IIVV
; 0.94 ; IVVKA
; 0.004 FIXED ; IIVF
; 0.02 ; IIVALAG
$SIGMA 0.0290039 ; epsPROP1
;0.000365773 ; epsADD1
$ESTIMATION METHOD=1 INTER MAXEVAL=9999 PRINT=5 SIG=3 POSTHOC
; standard error of estimates :
$COVARIANCE
$TABLE ID SEX WT AGE TIME DV PRED CPRED IPRED EVID RES WRES IRES
IWRES CWRES NPDE ESAMPLE=300 NOPRINT FILE=pred
; population and individual predictions and residuals
$TABLE ID SEX WT AGE CL V KA ETA(1) ETA(2) NOPRINT NOAPPEND
FIRSTONLY FILE=param
; individual PK parameters (bayesiens,posthoc)


NM-TRAN MESSAGES

WARNINGS AND ERRORS (IF ANY) FOR PROBLEM 1

(WARNING 2) NM-TRAN INFERS THAT THE DATA ARE POPULATION.

License Registered to: Universite de Namur
Expiration Date: 14 MAY 2021
Current Date: 17 AUG 2020
Days until program expires : 272
1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) VERSION 7.3.0
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
HCQ 1CMT ORAL PK MODEL (BASED ON CARMICHAEL ET AL (2003))
0DATA CHECKOUT RUN: NO
DATA SET LOCATED ON UNIT NO.: 2
THIS UNIT TO BE REWOUND: NO
NO. OF DATA RECS IN DATA SET: 11875
NO. OF DATA ITEMS IN DATA SET: 12
ID DATA ITEM IS DATA ITEM NO.: 1
DEP VARIABLE IS DATA ITEM NO.: 10
MDV DATA ITEM IS DATA ITEM NO.: 11
0INDICES PASSED TO SUBROUTINE PRED:
12 5 6 0 0 8 9 0 0 0 7
0LABELS FOR DATA ITEMS:
ID SEX WT AGE TIME AMT ADDL II CMT DV MDV EVID
0(NONBLANK) LABELS FOR PRED-DEFINED ITEMS:
CL V KA IPRED IRES IWRES
0FORMAT FOR DATA:
(E3.0,E2.0,E5.0,E3.0,E6.0,E4.0,E2.0,E3.0,E2.0,E7.0,2E2.0)

TOT. NO. OF OBS RECS: 76
TOT. NO. OF INDIVIDUALS: 48
0LENGTH OF THETA: 5
0DEFAULT THETA BOUNDARY TEST OMITTED: NO
0OMEGA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 2
0DEFAULT OMEGA BOUNDARY TEST OMITTED: NO
0SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 1
0DEFAULT SIGMA BOUNDARY TEST OMITTED: NO
0INITIAL ESTIMATE OF THETA:
LOWER BOUND INITIAL EST UPPER BOUND
0.0000E+00 0.1492E+02 0.1000E+07
0.0000E+00 0.8614E+03 0.1000E+07
0.0000E+00 0.9302E+01 0.1000E+02
0.7460E+00 0.7460E+00 0.7460E+00
-0.1000E+07 0.1204E+01 0.1000E+07
0INITIAL ESTIMATE OF OMEGA:
0.1631E+00
0.0000E+00 0.2710E+00
0INITIAL ESTIMATE OF SIGMA:
0.2900E-01
0COVARIANCE STEP OMITTED: NO
EIGENVLS. PRINTED: NO
SPECIAL COMPUTATION: NO
COMPRESSED FORMAT: NO
SIGDIGITS ETAHAT (SIGLO): -1
SIGDIGITS GRADIENTS (SIGL): -1
RELATIVE TOLERANCE (TOL): -1
ABSOLUTE TOLERANCE-ADVAN 9,13 ONLY (ATOL): -1
EXCLUDE COV FOR FOCE (NOFCOV): NO
RESUME COV ANALYSIS (RESUME): NO
0TABLES STEP OMITTED: NO
NO. OF TABLES: 2
SEED NUMBER (SEED): 11456
RANMETHOD:
MC SAMPLES (ESEED): 300
WRES SQUARE ROOT TYPE: EIGENVALUE
0-- TABLE 1 --
PRINTED: NO
HEADERS: YES
FILE TO BE FORWARDED: NO
FORMAT: S1PE11.4
LFORMAT:
RFORMAT:
0USER-CHOSEN ITEMS:
ID SEX WT AGE TIME DV CPRED IPRED EVID IRES IWRES CWRES NPDE
0-- TABLE 2 --
0FIRST RECORDS ONLY: YES
04 COLUMNS APPENDED: NO
PRINTED: NO
HEADERS: YES
FILE TO BE FORWARDED: NO
FORMAT: S1PE11.4
LFORMAT:
RFORMAT:
0USER-CHOSEN ITEMS:
ID SEX WT AGE CL V KA ETA1 ETA2
1DOUBLE PRECISION PREDPP VERSION 7.3.0

ONE COMPARTMENT MODEL WITH FIRST-ORDER ABSORPTION (ADVAN2)
0MAXIMUM NO. OF BASIC PK PARAMETERS: 3
0BASIC PK PARAMETERS (AFTER TRANSLATION):
ELIMINATION RATE (K) IS BASIC PK PARAMETER NO.: 1
ABSORPTION RATE (KA) IS BASIC PK PARAMETER NO.: 3

TRANSLATOR WILL CONVERT PARAMETERS
CLEARANCE (CL) AND VOLUME (V) TO K (TRANS2)
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 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 * 4 * * *
2 5 * * * *
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.: 12
TIME DATA ITEM IS DATA ITEM NO.: 5
DOSE AMOUNT DATA ITEM IS DATA ITEM NO.: 6
INTERVAL DATA ITEM IS DATA ITEM NO.: 8
ADDL. DOSES DATA ITEM IS DATA ITEM NO.: 7
COMPT. NO. DATA ITEM IS DATA ITEM NO.: 9

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
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: 3
INTERMEDIATE PRINTOUT: YES
ESTIMATE OUTPUT TO MSF: 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): 100
GRADIENT SIGDIGITS OF
FIXED EFFECTS PARAMETERS (SIGL): 100
EXCLUDE TITLE (NOTITLE): NO
EXCLUDE COLUMN LABELS (NOLABEL): NO
NOPRIOR SETTING (NOPRIOR): OFF
NOCOV SETTING (NOCOV): OFF
DERCONT SETTING (DERCONT): OFF
ABSOLUTE TOLERANCE-ADVAN 9,13 ONLY(ATOL):-100
FINAL ETA RE-EVALUATION (FNLETA): ON
EXCLUDE NON-INFLUENTIAL (NON-INFL.) ETAS
IN SHRINKAGE (ETASTYPE): NO
NON-INFL. ETA CORRECTION (NONINFETA): OFF
FORMAT FOR ADDITIONAL FILES (FORMAT): S1PE12.5
PARAMETER ORDER FOR OUTPUTS (ORDER): TSOL
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: 866.780792971716 NO. OF FUNC. EVALS.: 7
CUMULATIVE NO. OF FUNC. EVALS.: 7
NPARAMETR: 1.4921E+01 8.6138E+02 9.3023E+00 1.2041E+00 1.6313E-01 2.7101E-01 2.9004E-02
PARAMETER: 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01
GRADIENT: -1.9609E+01 -6.1557E+00 -4.0211E-03 -3.4866E+01 2.7114E+00 2.1116E-01 1.9357E+00

0ITERATION NO.: 5 OBJECTIVE VALUE: 865.932999987325 NO. OF FUNC. EVALS.: 8
CUMULATIVE NO. OF FUNC. EVALS.: 51
NPARAMETR: 1.5918E+01 8.6217E+02 9.3023E+00 1.3799E+00 1.4779E-01 2.7466E-01 2.8750E-02
PARAMETER: 1.6471E-01 1.0091E-01 1.0001E-01 1.1460E-01 5.0632E-02 1.0668E-01 9.5606E-02
GRADIENT: 4.8823E+00 1.6354E+00 8.3841E-04 4.1421E+00 -2.7152E-01 3.9762E-01 -1.3448E-01

0ITERATION NO.: 10 OBJECTIVE VALUE: 865.901660278475 NO. OF FUNC. EVALS.: 13
CUMULATIVE NO. OF FUNC. EVALS.: 97
NPARAMETR: 1.5717E+01 8.6043E+02 9.3026E+00 1.3720E+00 1.4872E-01 2.7180E-01 2.8619E-02
PARAMETER: 1.5202E-01 9.8890E-02 1.0039E-01 1.1395E-01 5.3761E-02 1.0146E-01 9.3320E-02
GRADIENT: -2.2803E-01 -7.5451E-02 -1.4970E-04 -1.0164E+00 -1.3533E-03 1.0568E-03 -1.5551E-02

0ITERATION NO.: 12 OBJECTIVE VALUE: 865.901370475309 NO. OF FUNC. EVALS.: 10
CUMULATIVE NO. OF FUNC. EVALS.: 120
NPARAMETR: 1.5721E+01 8.6078E+02 9.3026E+00 1.3785E+00 1.4873E-01 2.7175E-01 2.8645E-02
PARAMETER: 1.5222E-01 9.9292E-02 1.0043E-01 1.1448E-01 5.3793E-02 1.0136E-01 9.3783E-02
GRADIENT: -2.0615E-03 -7.2320E-03 -8.2032E-05 1.0074E-01 6.5124E-03 1.1503E-03 3.6032E-03

#TERM:
0MINIMIZATION SUCCESSFUL
NO. OF FUNCTION EVALUATIONS USED: 120
NO. OF SIG. DIGITS IN FINAL EST.: 3.1

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: 2.0383E-03 -3.1903E-02
SE: 4.2241E-02 5.3895E-02
N: 48 48

P VAL.: 9.6151E-01 5.5388E-01

ETAshrink(%): 2.3312E+01 2.7614E+01
EBVshrink(%): 2.4480E+01 2.9753E+01
EPSshrink(%): 4.0741E+01

#TERE:
Elapsed estimation time in seconds: 26.44
0R MATRIX ALGORITHMICALLY SINGULAR
AND ALGORITHMICALLY NON-POSITIVE-SEMIDEFINITE
0R MATRIX IS OUTPUT
0COVARIANCE STEP ABORTED
Elapsed covariance time in seconds: 41.73
1




















************************************************************************************************************************
******************** ********************
******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ********************
#OBJT:************** MINIMUM VALUE OF OBJECTIVE FUNCTION ********************
******************** ********************
************************************************************************************************************************






#OBJV:******************************************** 865.901 **************************************************
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

1.57E+01 8.61E+02 9.30E+00 7.46E-01 1.38E+00



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


ETA1 ETA2

ETA1
+ 1.49E-01

ETA2
+ 0.00E+00 2.72E-01



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


EPS1

EPS1
+ 2.86E-02

1


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


ETA1 ETA2

ETA1
+ 3.86E-01

ETA2
+ 0.00E+00 5.21E-01



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


EPS1

EPS1
+ 1.69E-01

1
************************************************************************************************************************
******************** ********************
******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ********************
******************** R MATRIX ********************
******************** ********************
************************************************************************************************************************


TH 1 TH 2 TH 3 TH 4 TH 5 OM11 OM12 OM22 SG11

TH 1
+ 7.16E-01

TH 2
+ 3.57E-03 1.15E-04

TH 3
+ 1.95E-02 5.02E-05 -1.25E+00

TH 4
+ ......... ......... ......... .........

TH 5
+ 6.06E-01 -6.08E-04 7.23E-02 ......... 6.88E+00

OM11
+ -2.11E-01 -4.05E-02 2.27E-02 ......... 1.88E+00 4.72E+02

OM12
+ ......... ......... ......... ......... ......... ......... .........

OM22
+ 1.92E-03 1.30E-02 -9.67E-03 ......... -4.28E-01 3.21E+01 ......... 1.27E+02

SG11
+ -1.13E+01 -2.44E-01 -2.39E+01 ......... -3.61E+00 4.20E+02 ......... 2.09E+02 1.18E+04

#CPUT: Total CPU Time in Seconds, 73.375
Stop Time:
17-08-20
15:41
