********************************************************************************
*                           TMDD_final.mlxtran                                 *
*                            at                                                *
*                           Monolix version : 2024R1                           *
********************************************************************************


ESTIMATION OF THE POPULATION PARAMETERS ________________________________________

Fixed Effects ----------------------------     se_lin     rse(%)   P2.5_lin  P97.5_lin
F_pop                 :               0.72
D50_pop               :               91.8        169        185       14.6        578
TLAG_pop              :                0.1
KA_pop                :             0.0807     0.0133       16.5     0.0588      0.111
V_pop                 :              0.627      0.457       72.9      0.205       1.92
CLpop_pop             :              0.714      0.467       65.4      0.253       2.01
etaCL_pop             :                  0
KDEG_pop              :               2.03      0.143       7.07       1.77       2.33
PCSK90_pop            :               4.06      0.283       6.96       3.55       4.65
beta_PCSK90_HEALTHY_1 :             -0.232     0.0977         42     -0.424     -0.041
KSS_pop               :              0.374     0.0591       15.8      0.276      0.507
KINT_pop              :             0.0526    0.00172       3.27     0.0494     0.0561
KOUT_pop              :              0.321     0.0122       3.81      0.298      0.346
LDLC0_pop             :                116          3       2.59        110        122
IMAX_pop              :               0.88     0.0282        3.2      0.814      0.924
IC50_pop              :               1.36      0.212       15.5       1.01       1.84

Standard Deviation of the Random Effects -
omega_F               :               1.51      0.204       13.6       1.16       1.96
omega_KA              :               1.16      0.116       10.1      0.952       1.41
omega_V               :               1.44       0.21       14.5       1.09       1.91
omega_etaCL           :              0.645      0.105       16.2      0.472      0.881
omega_PCSK90          :              0.319      0.038       11.9      0.253      0.402
omega_KSS             :               1.04      0.107       10.3      0.852       1.27
omega_LDLC0           :              0.183     0.0187       10.2       0.15      0.223
omega_IMAX            :              0.736      0.205       27.8      0.438       1.23
omega_IC50            :              0.287       0.16       55.8      0.114      0.724

Error Model Parameters -------------------
a2                    :              1e-05
b2                    :              0.391    0.00941        2.4      0.373       0.41
a3                    :              1e-05
b3                    :              0.407    0.00935        2.3      0.389      0.426
a4                    :               5.92      0.768         13       4.61       7.61
b4                    :              0.128    0.00606       4.72      0.117      0.141

Elapsed time (seconds):  6.3e+02
Exploratory phase iterations:      277 (Autostop)
Smoothing phase iterations:        200 (Stopped at the maximum number of iterations)

 _______________________________________________________________________________



ESTIMATION OF THE INDIVIDUAL PARAMETERS ________________________________________


Estimation of the individual parameters by Conditional Distribution ------------
                   min            Q1        median            Q3           max  shrinkage(%)
F      :         0.105         0.637          1.34          4.47          26.9            18
D50    :          91.8          91.8          91.8          91.8          91.8           nan
TLAG   :           0.1           0.1           0.1           0.1           0.1           nan
KA     :       0.00483        0.0449        0.0909         0.214         0.867         0.793
V      :        0.0424         0.304         0.707          2.07          13.8          10.3
CLpop  :         0.714         0.714         0.714         0.714         0.714           nan
etaCL  :        -0.965        -0.553        -0.168         0.211         0.633          29.8
KDEG   :          2.03          2.03          2.03          2.03          2.03           nan
PCSK90 :          2.02          2.87          3.65          4.47          8.91          1.67
KSS    :        0.0303         0.142         0.424         0.757          3.15         0.585
KINT   :        0.0526        0.0526        0.0526        0.0526        0.0526           nan
KOUT   :         0.321         0.321         0.321         0.321         0.321           nan
LDLC0  :          78.9           102           115           134           161        -0.119
IMAX   :         0.609         0.839         0.873         0.902         0.932            37
IC50   :         0.999           1.3           1.4          1.52           1.8          57.2

Elapsed time (seconds):  1.7e+02
Iterations:      283 (Autostop)

 -------------------------------------------------------------------------------


Estimation of the individual parameters by Conditional Mode --------------------
                   min            Q1        median            Q3           max  shrinkage(%)
F      :         0.101         0.563         0.966          3.41          10.3          31.3
D50    :          91.8          91.8          91.8          91.8          91.8           nan
TLAG   :           0.1           0.1           0.1           0.1           0.1           nan
KA     :        0.0039         0.041        0.0918         0.184         0.968         0.506
V      :        0.0643         0.258         0.463          1.06          3.56          35.6
CLpop  :         0.714         0.714         0.714         0.714         0.714           nan
etaCL  :         -1.02         -0.77        -0.411        0.0311         0.503          34.5
KDEG   :          2.03          2.03          2.03          2.03          2.03           nan
PCSK90 :          1.97          2.93           3.6          4.39          8.95        -0.428
KSS    :        0.0298         0.138         0.389         0.652          2.79         0.259
KINT   :        0.0526        0.0526        0.0526        0.0526        0.0526           nan
KOUT   :         0.321         0.321         0.321         0.321         0.321           nan
LDLC0  :          78.8           103           115           135           162          1.21
IMAX   :         0.658         0.846         0.882         0.909         0.936          34.6
IC50   :         0.999          1.26          1.35          1.45          1.94          56.9

Elapsed time (seconds):      4.3

 -------------------------------------------------------------------------------

 _______________________________________________________________________________



ESTIMATION OF THE FISHER INFORMATION MATRIX ____________________________________


Estimation of the Fisher information matrix by Linearization -------------------

Correlation Matrix :
              D50_pop         1
               KA_pop -0.012676         1
                V_pop   0.86292 0.0032701         1
            CLpop_pop   0.86445 -0.013585   0.88453         1
             KDEG_pop -0.042444  -0.01489 -0.051686 -0.062455         1
           PCSK90_pop-0.0056579-0.0050488   -0.0186-0.0065885 -0.043684         1
beta_PCSK90_HEALTHY_1 0.0028066 0.0010145 0.0080575 0.0036681  0.010615  -0.69709         1
              KSS_pop  0.024918  0.010113     0.037  0.027924  -0.30233 -0.080831  0.041601         1
             KINT_pop -0.044985  0.013157 -0.041347 -0.072226   0.57293-0.0046423  0.015095    -0.136         1
             KOUT_pop-0.0010424 -0.010138-0.0026574-0.0050638-0.00074863  0.024539-0.0077741-0.0001899   0.12005         1
            LDLC0_pop-0.0021444-0.0006893-0.0034629-0.0022161 0.0025436 0.0082543 -0.003175-0.0080505  0.013706  0.066958         1
             IMAX_pop 0.0070125 0.0023179  0.014962 0.0058219   0.11691  -0.14506   0.07925  0.043919  0.028298 0.0059023  0.072343         1
             IC50_pop 0.0059537-0.0039128 0.0072467 0.0020936  0.072695  -0.01372  0.027289 0.0045448  0.051917   0.11357  0.022818   0.73001         1
              omega_F         0         0         0         0         0         0         0         0         0         0         0         0         0         1
             omega_KA         0         0         0         0         0         0         0         0         0         0         0         0         0-0.0014172         1
              omega_V         0         0         0         0         0         0         0         0         0         0         0         0         0  -0.17964-0.0028107         1
          omega_etaCL         0         0         0         0         0         0         0         0         0         0         0         0         0  -0.12859 -0.001438  -0.13772         1
         omega_PCSK90         0         0         0         0         0         0         0         0         0         0         0         0         0-4.9963e-05-0.00014142-0.000945861.6449e-05         1
            omega_KSS         0         0         0         0         0         0         0         0         0         0         0         0         0-0.0003885-4.7455e-05-0.0022366-1.7315e-05-0.0076887         1
          omega_LDLC0         0         0         0         0         0         0         0         0         0         0         0         0         0-4.3895e-064.3246e-08-5.1086e-051.8318e-06-0.00028675-0.00029195         1
           omega_IMAX         0         0         0         0         0         0         0         0         0         0         0         0         0-0.00011368-7.0972e-05-0.00028643-1.3234e-05 -0.025111-0.0053822-0.0060458         1
           omega_IC50         0         0         0         0         0         0         0         0         0         0         0         0         0-5.9272e-06-0.000122742.9297e-05-4.3285e-05 -0.0157230.00062101 -0.001168   -0.5325         1
                   b2         0         0         0         0         0         0         0         0         0         0         0         0         0-0.00038635-0.0053065-0.0058867-0.0036412-0.0042054-0.0034209-9.496e-05 -0.003263-0.00090284         1
                   b3         0         0         0         0         0         0         0         0         0         0         0         0         0-0.00012224-0.0024125-0.0022895-0.00044024 -0.026828-0.0054442-0.00025693-0.0089935-0.0028184 -0.020366         1
                   a4         0         0         0         0         0         0         0         0         0         0         0         0         0-8.9413e-06-7.6899e-050.000127435.6426e-050.000397720.00065729  0.005246 0.0029697 -0.023806-0.00026272-3.6464e-05         1
                   b4         0         0         0         0         0         0         0         0         0         0         0         0         0-3.6587e-05-0.00019133-0.00039535-0.0001302-0.00058166-0.0016876 -0.012312 -0.017836 0.0028422-0.0015093-0.0015745  -0.77911         1

                               min       max   max/min
Eigen values           :      0.11       2.8        24

Elapsed time (seconds):      2.5

 -------------------------------------------------------------------------------

 _______________________________________________________________________________



ESTIMATION OF THE LOG-LIKELIHOOD _______________________________________________

                                                           (lin)
-2 x log-likelihood                       (OFV) :       11603.44
Akaike Information Criteria               (AIC) :       11655.44
Corrected Bayesian Information Criteria  (BICc) :       11772.39
Bayesian Information Criteria             (BIC) :       11707.15

Elapsed time                          (seconds) :           1.49
CPU time                              (seconds) :           9.00

 _______________________________________________________________________________

DATASET INFORMATION
Number of individuals: 54
Number of observations (obsid 2): 1026
Number of observations (obsid 3): 1080
Number of observations (obsid 4): 1080
Number of doses: 162

