
===================================== 
  Initial design 
===================================== 

      Arms name Number of subjects Outcome Dose                    Sampling times
1 armConstraint                 30  RespPK 6.32     (0.25, 0.75, 1, 1.5, 2, 4, 6)
2 armConstraint                 30  RespPD    . (0.25, 0.75, 1.5, 2, 3, 6, 8, 12)

*************************************** 
 Population Fisher Matrix 
*************************************** 

                         μ_V          μ_Cl        μ_kout        μ_Imax       μ_IC50     μ_gamma         ω²_V        ω²_Cl      ω²_kout      ω²_Imax      ω²_IC50     ω²_gamma σ_slope_RespPK
μ_V            483.943136181 -2.515935e+01 -0.0021215242 -10.359410838  1.436756981  0.01963642 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00   0.000000e+00
μ_Cl           -25.159351796  1.783803e+03 -0.0006308506  -3.299783812  0.494965586  0.28030930 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00   0.000000e+00
μ_kout          -0.002121524 -6.308506e-04  0.8845243295   0.009428532 -0.001235346 -0.01067545 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00   0.000000e+00
μ_Imax         -10.359410838 -3.299784e+00  0.0094285322  44.462907428 -6.214531153 -0.71598124 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00   0.000000e+00
μ_IC50           1.436756981  4.949656e-01 -0.0012353465  -6.214531153  0.892950381  0.23982726 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00   0.000000e+00
μ_gamma          0.019636419  2.803093e-01 -0.0106754464  -0.715981240  0.239827262  1.05954052 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00 0.000000e+00   0.000000e+00
ω²_V             0.000000000  0.000000e+00  0.0000000000   0.000000000  0.000000000  0.00000000 1.170481e+03 4.529259e-01 1.548620e-06 5.657304e-01 1.601551e+00 2.700202e-05   1.414551e+02
ω²_Cl            0.000000000  0.000000e+00  0.0000000000   0.000000000  0.000000000  0.00000000 4.529259e-01 3.259676e+02 1.960445e-08 8.217940e-03 2.721302e-02 7.877698e-04   1.987900e+01
ω²_kout          0.000000000  0.000000e+00  0.0000000000   0.000000000  0.000000000  0.00000000 1.548620e-06 1.960445e-08 1.853283e+01 3.226271e-05 8.151263e-05 5.494360e-04   1.063131e-05
ω²_Imax          0.000000000  0.000000e+00  0.0000000000   0.000000000  0.000000000  0.00000000 5.657304e-01 8.217940e-03 3.226271e-05 1.099256e+01 3.160491e+01 3.786507e-02   3.861180e+00
ω²_IC50          0.000000000  0.000000e+00  0.0000000000   0.000000000  0.000000000  0.00000000 1.601551e+00 2.721302e-02 8.151263e-05 3.160491e+01 9.603446e+01 6.252695e-01   1.087403e+01
ω²_gamma         0.000000000  0.000000e+00  0.0000000000   0.000000000  0.000000000  0.00000000 2.700202e-05 7.877698e-04 5.494360e-04 3.786507e-02 6.252695e-01 1.101547e+00   5.667870e-02
σ_slope_RespPK   0.000000000  0.000000e+00  0.0000000000   0.000000000  0.000000000  0.00000000 1.414551e+02 1.987900e+01 1.063131e-05 3.861180e+00 1.087403e+01 5.667870e-02   6.839433e+03
σ_inter_RespPD   0.000000000  0.000000e+00  0.0000000000   0.000000000  0.000000000  0.00000000 5.017060e-02 5.310514e-04 1.061828e-02 7.675634e-01 1.874276e+00 1.056648e-01   4.046508e-01
               σ_inter_RespPD
μ_V              0.0000000000
μ_Cl             0.0000000000
μ_kout           0.0000000000
μ_Imax           0.0000000000
μ_IC50           0.0000000000
μ_gamma          0.0000000000
ω²_V             0.0501706038
ω²_Cl            0.0005310514
ω²_kout          0.0106182763
ω²_Imax          0.7675634046
ω²_IC50          1.8742757046
ω²_gamma         0.1056648445
σ_slope_RespPK   0.4046508170
σ_inter_RespPD   3.3502933639

*************************************** 
 Fixed effects 
*************************************** 

                  μ_V          μ_Cl        μ_kout        μ_Imax       μ_IC50     μ_gamma
μ_V     483.943136181 -2.515935e+01 -0.0021215242 -10.359410838  1.436756981  0.01963642
μ_Cl    -25.159351796  1.783803e+03 -0.0006308506  -3.299783812  0.494965586  0.28030930
μ_kout   -0.002121524 -6.308506e-04  0.8845243295   0.009428532 -0.001235346 -0.01067545
μ_Imax  -10.359410838 -3.299784e+00  0.0094285322  44.462907428 -6.214531153 -0.71598124
μ_IC50    1.436756981  4.949656e-01 -0.0012353465  -6.214531153  0.892950381  0.23982726
μ_gamma   0.019636419  2.803093e-01 -0.0106754464  -0.715981240  0.239827262  1.05954052

*************************************** 
 Variance components 
*************************************** 

                       ω²_V        ω²_Cl      ω²_kout      ω²_Imax      ω²_IC50     ω²_gamma σ_slope_RespPK σ_inter_RespPD
ω²_V           1.170481e+03 4.529259e-01 1.548620e-06 5.657304e-01 1.601551e+00 2.700202e-05   1.414551e+02   0.0501706038
ω²_Cl          4.529259e-01 3.259676e+02 1.960445e-08 8.217940e-03 2.721302e-02 7.877698e-04   1.987900e+01   0.0005310514
ω²_kout        1.548620e-06 1.960445e-08 1.853283e+01 3.226271e-05 8.151263e-05 5.494360e-04   1.063131e-05   0.0106182763
ω²_Imax        5.657304e-01 8.217940e-03 3.226271e-05 1.099256e+01 3.160491e+01 3.786507e-02   3.861180e+00   0.7675634046
ω²_IC50        1.601551e+00 2.721302e-02 8.151263e-05 3.160491e+01 9.603446e+01 6.252695e-01   1.087403e+01   1.8742757046
ω²_gamma       2.700202e-05 7.877698e-04 5.494360e-04 3.786507e-02 6.252695e-01 1.101547e+00   5.667870e-02   0.1056648445
σ_slope_RespPK 1.414551e+02 1.987900e+01 1.063131e-05 3.861180e+00 1.087403e+01 5.667870e-02   6.839433e+03   0.4046508170
σ_inter_RespPD 5.017060e-02 5.310514e-04 1.061828e-02 7.675634e-01 1.874276e+00 1.056648e-01   4.046508e-01   3.3502933639

********************************************* 
 Determinant, condition numbers and D-criterion  
*********************************************** 

Determinant: 1892186514468350720 
D-criterion: 20.2067944869215 
Condition number of the fixed effects: 323832.174335363 
Condition number of the random effects: 14200.0226338072 

*************************************** 
 Parameters estimation 
*************************************** 

               parametersValues          SE        RSE
μ_V                    0.740000  0.04559038   6.160862
μ_Cl                   0.280000  0.02368822   8.460077
μ_kout                 6.140000  1.06357081  17.322000
μ_Imax                 0.760000  1.82700380 240.395237
μ_IC50                 9.220000 13.23044351 143.497218
μ_gamma                2.770000  2.01694542  72.813914
ω²_V                   0.099856  0.02926613  29.308334
ω²_Cl                  0.207936  0.05539254  26.639224
ω²_kout                0.896809  0.23228946  25.901776
ω²_Imax                0.192721  1.33935341 694.970141
ω²_IC50                0.204304  0.45266182 221.562877
ω²_gamma               3.101121  0.97863817  31.557562
σ_slope_RespPK         0.210000  0.01210916   5.766266
σ_inter_RespPD         9.600000  0.55405294   5.771385

===================================== 
  Optimal design 
===================================== 

   Arms name Number of subjects Outcome  Dose     Sampling times
1     Arm667               0.64  RespPK 11.24    (0.25, 1, 4, 6)
2     Arm667               0.64  RespPD     .    (0.75, 2, 3, 6)
3     Arm837               0.88  RespPK    20    (0.25, 1, 4, 6)
4     Arm837               0.88  RespPD     .   (0.75, 2, 6, 12)
5     Arm817               1.77  RespPK    20    (0.25, 1, 4, 6)
6     Arm817               1.77  RespPD     .    (0.75, 2, 3, 6)
7     Arm664               5.82  RespPK 11.24 (0.25, 0.75, 4, 6)
8     Arm664               5.82  RespPD     .    (0.75, 2, 3, 6)
9     Arm834               7.18  RespPK    20 (0.25, 0.75, 4, 6)
10    Arm834               7.18  RespPD     .   (0.75, 2, 6, 12)
11    Arm814              13.71  RespPK    20 (0.25, 0.75, 4, 6)
12    Arm814              13.71  RespPD     .    (0.75, 2, 3, 6)

*************************************** 
 Population Fisher Matrix 
*************************************** 

                        μ_V          μ_Cl      μ_kout     μ_Imax      μ_IC50      μ_gamma         ω²_V        ω²_Cl      ω²_kout      ω²_Imax      ω²_IC50     ω²_gamma σ_slope_RespPK σ_inter_RespPD
μ_V            441.94766215 -5.733100e+01 -0.01236585  -6.688188  1.17545168 -0.403675305 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_Cl           -57.33099676  1.757901e+03 -0.04910061  -4.563042  1.58876877  0.005979464 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_kout          -0.01236585 -4.910061e-02  0.87055103   0.767240 -0.03072718 -0.047741108 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_Imax          -6.68818843 -4.563042e+00  0.76723997 149.841076 -3.27482827  4.643952232 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_IC50           1.17545168  1.588769e+00 -0.03072718  -3.274828  1.05291300 -0.026930370 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_gamma         -0.40367531  5.979464e-03 -0.04774111   4.643952 -0.02693037  0.945572176 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
ω²_V             0.00000000  0.000000e+00  0.00000000   0.000000  0.00000000  0.000000000 9.761645e+02 2.352061e+00 6.426557e-05   0.35962926   1.14226753 0.0119071393   2.154440e+02    0.016465616
ω²_Cl            0.00000000  0.000000e+00  0.00000000   0.000000  0.00000000  0.000000000 2.352061e+00 3.165700e+02 1.333508e-04   0.02662137   0.28893220 0.0001551839   2.626014e+01    0.005516857
ω²_kout          0.00000000  0.000000e+00  0.00000000   0.000000  0.00000000  0.000000000 6.426557e-05 1.333508e-04 1.795348e+01   0.27612949   0.05581461 0.0141175668   7.505416e-03    0.041594169
ω²_Imax          0.00000000  0.000000e+00  0.00000000   0.000000  0.00000000  0.000000000 3.596293e-01 2.662137e-02 2.761295e-01 129.99710162  14.59817254 1.7306834484   1.474160e+00    1.964070533
ω²_IC50          0.00000000  0.000000e+00  0.00000000   0.000000  0.00000000  0.000000000 1.142268e+00 2.889322e-01 5.581461e-02  14.59817254 137.15736498 0.0800695183   1.144645e+01    2.550765126
ω²_gamma         0.00000000  0.000000e+00  0.00000000   0.000000  0.00000000  0.000000000 1.190714e-02 1.551839e-04 1.411757e-02   1.73068345   0.08006952 0.8875950952   8.590151e-02    0.104646111
σ_slope_RespPK   0.00000000  0.000000e+00  0.00000000   0.000000  0.00000000  0.000000000 2.154440e+02 2.626014e+01 7.505416e-03   1.47416000  11.44645305 0.0859015137   2.796442e+03    0.230205164
σ_inter_RespPD   0.00000000  0.000000e+00  0.00000000   0.000000  0.00000000  0.000000000 1.646562e-02 5.516857e-03 4.159417e-02   1.96407053   2.55076513 0.1046461108   2.302052e-01    0.428440823

*************************************** 
 Fixed effects 
*************************************** 

                 μ_V          μ_Cl      μ_kout     μ_Imax      μ_IC50      μ_gamma
μ_V     441.94766215 -5.733100e+01 -0.01236585  -6.688188  1.17545168 -0.403675305
μ_Cl    -57.33099676  1.757901e+03 -0.04910061  -4.563042  1.58876877  0.005979464
μ_kout   -0.01236585 -4.910061e-02  0.87055103   0.767240 -0.03072718 -0.047741108
μ_Imax   -6.68818843 -4.563042e+00  0.76723997 149.841076 -3.27482827  4.643952232
μ_IC50    1.17545168  1.588769e+00 -0.03072718  -3.274828  1.05291300 -0.026930370
μ_gamma  -0.40367531  5.979464e-03 -0.04774111   4.643952 -0.02693037  0.945572176

*************************************** 
 Variance components 
*************************************** 

                       ω²_V        ω²_Cl      ω²_kout      ω²_Imax      ω²_IC50     ω²_gamma σ_slope_RespPK σ_inter_RespPD
ω²_V           9.761645e+02 2.352061e+00 6.426557e-05   0.35962926   1.14226753 0.0119071393   2.154440e+02    0.016465616
ω²_Cl          2.352061e+00 3.165700e+02 1.333508e-04   0.02662137   0.28893220 0.0001551839   2.626014e+01    0.005516857
ω²_kout        6.426557e-05 1.333508e-04 1.795348e+01   0.27612949   0.05581461 0.0141175668   7.505416e-03    0.041594169
ω²_Imax        3.596293e-01 2.662137e-02 2.761295e-01 129.99710162  14.59817254 1.7306834484   1.474160e+00    1.964070533
ω²_IC50        1.142268e+00 2.889322e-01 5.581461e-02  14.59817254 137.15736498 0.0800695183   1.144645e+01    2.550765126
ω²_gamma       1.190714e-02 1.551839e-04 1.411757e-02   1.73068345   0.08006952 0.8875950952   8.590151e-02    0.104646111
σ_slope_RespPK 2.154440e+02 2.626014e+01 7.505416e-03   1.47416000  11.44645305 0.0859015137   2.796442e+03    0.230205164
σ_inter_RespPD 1.646562e-02 5.516857e-03 4.159417e-02   1.96407053   2.55076513 0.1046461108   2.302052e-01    0.428440823

********************************************* 
 Determinant, condition numbers and D-criterion  
*********************************************** 

Determinant: 6.31315138109825e+21 
D-criterion: 36.0711877593656 
Condition number of the fixed effects: 2376.71661961602 
Condition number of the random effects: 8155.99219628966 

*************************************** 
 Parameters estimation 
*************************************** 

               parametersValues         SE       RSE
μ_V                    0.740000 0.04775536  6.453427
μ_Cl                   0.280000 0.02392115  8.543267
μ_kout                 6.140000 1.07821075 17.560436
μ_Imax                 0.760000 0.09256982 12.180240
μ_IC50                 9.220000 1.01515063 11.010311
μ_gamma                2.770000 1.12502992 40.614799
ω²_V                   0.099856 0.03228218 32.328733
ω²_Cl                  0.207936 0.05622566 27.039889
ω²_kout                0.896809 0.23603646 26.319591
ω²_Imax                0.192721 0.09164467 47.553026
ω²_IC50                0.204304 0.09073074 44.409674
ω²_gamma               3.101121 1.08695256 35.050311
σ_slope_RespPK         0.210000 0.01908354  9.087401
σ_inter_RespPD         9.600000 1.68756908 17.578845
