
===================================== 
  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      Arm1               9.97  RespPK    20 (0.25, 0.75, 4, 6)
2      Arm1               9.97  RespPD     .   (0.75, 2, 6, 12)
3      Arm2               13.3  RespPK    20 (0.25, 0.75, 4, 6)
4      Arm2               13.3  RespPD     .    (0.75, 2, 3, 6)
5      Arm3               6.73  RespPK 11.24 (0.25, 0.75, 4, 6)
6      Arm3               6.73  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            442.42767946 -5.722735e+01 -0.01283957  -6.7730365  1.15398862 -0.405928724 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_Cl           -57.22735145  1.757798e+03 -0.04702067  -4.7644365  1.54590129  0.005111016 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_kout          -0.01283957 -4.702067e-02  0.87179742   0.7062229 -0.02945391 -0.044150390 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_Imax          -6.77303648 -4.764437e+00  0.70622291 151.9673571 -3.40928835  4.462377068 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_IC50           1.15398862  1.545901e+00 -0.02945391  -3.4092884  1.02517615 -0.028420509 0.000000e+00 0.000000e+00 0.000000e+00   0.00000000   0.00000000 0.0000000000   0.000000e+00    0.000000000
μ_gamma         -0.40592872  5.111016e-03 -0.04415039   4.4623771 -0.02842051  0.955210290 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   0.0000000  0.00000000  0.000000000 9.782766e+02 2.343473e+00 6.785969e-05   0.36834443   1.11109049 0.0120839481   2.147356e+02    0.016637130
ω²_Cl            0.00000000  0.000000e+00  0.00000000   0.0000000  0.00000000  0.000000000 2.343473e+00 3.165327e+02 1.231163e-04   0.02799261   0.27418887 0.0001660741   2.632674e+01    0.005574841
ω²_kout          0.00000000  0.000000e+00  0.00000000   0.0000000  0.00000000  0.000000000 6.785969e-05 1.231163e-04 1.800493e+01   0.24293648   0.05155276 0.0124677850   6.828079e-03    0.039470891
ω²_Imax          0.00000000  0.000000e+00  0.00000000   0.0000000  0.00000000  0.000000000 3.683444e-01 2.799261e-02 2.429365e-01 134.21483469  15.34076803 1.6048142318   1.525019e+00    1.977219903
ω²_IC50          0.00000000  0.000000e+00  0.00000000   0.0000000  0.00000000  0.000000000 1.111090e+00 2.741889e-01 5.155276e-02  15.34076803 130.36343842 0.0863674220   1.088414e+01    2.574826139
ω²_gamma         0.00000000  0.000000e+00  0.00000000   0.0000000  0.00000000  0.000000000 1.208395e-02 1.660741e-04 1.246779e-02   1.60481423   0.08636742 0.9052593492   8.729990e-02    0.105996297
σ_slope_RespPK   0.00000000  0.000000e+00  0.00000000   0.0000000  0.00000000  0.000000000 2.147356e+02 2.632674e+01 6.828079e-03   1.52501867  10.88414156 0.0872999001   2.795737e+03    0.232692783
σ_inter_RespPD   0.00000000  0.000000e+00  0.00000000   0.0000000  0.00000000  0.000000000 1.663713e-02 5.574841e-03 3.947089e-02   1.97721990   2.57482614 0.1059962969   2.326928e-01    0.426249789

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

                 μ_V          μ_Cl      μ_kout      μ_Imax      μ_IC50      μ_gamma
μ_V     442.42767946 -5.722735e+01 -0.01283957  -6.7730365  1.15398862 -0.405928724
μ_Cl    -57.22735145  1.757798e+03 -0.04702067  -4.7644365  1.54590129  0.005111016
μ_kout   -0.01283957 -4.702067e-02  0.87179742   0.7062229 -0.02945391 -0.044150390
μ_Imax   -6.77303648 -4.764437e+00  0.70622291 151.9673571 -3.40928835  4.462377068
μ_IC50    1.15398862  1.545901e+00 -0.02945391  -3.4092884  1.02517615 -0.028420509
μ_gamma  -0.40592872  5.111016e-03 -0.04415039   4.4623771 -0.02842051  0.955210290

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

                       ω²_V        ω²_Cl      ω²_kout      ω²_Imax      ω²_IC50     ω²_gamma σ_slope_RespPK σ_inter_RespPD
ω²_V           9.782766e+02 2.343473e+00 6.785969e-05   0.36834443   1.11109049 0.0120839481   2.147356e+02    0.016637130
ω²_Cl          2.343473e+00 3.165327e+02 1.231163e-04   0.02799261   0.27418887 0.0001660741   2.632674e+01    0.005574841
ω²_kout        6.785969e-05 1.231163e-04 1.800493e+01   0.24293648   0.05155276 0.0124677850   6.828079e-03    0.039470891
ω²_Imax        3.683444e-01 2.799261e-02 2.429365e-01 134.21483469  15.34076803 1.6048142318   1.525019e+00    1.977219903
ω²_IC50        1.111090e+00 2.741889e-01 5.155276e-02  15.34076803 130.36343842 0.0863674220   1.088414e+01    2.574826139
ω²_gamma       1.208395e-02 1.660741e-04 1.246779e-02   1.60481423   0.08636742 0.9052593492   8.729990e-02    0.105996297
σ_slope_RespPK 2.147356e+02 2.632674e+01 6.828079e-03   1.52501867  10.88414156 0.0872999001   2.795737e+03    0.232692783
σ_inter_RespPD 1.663713e-02 5.574841e-03 3.947089e-02   1.97721990   2.57482614 0.1059962969   2.326928e-01    0.426249789

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

Determinant: 6.36420159165367e+21 
D-criterion: 36.0919444747579 
Condition number of the fixed effects: 2312.37488361135 
Condition number of the random effects: 8272.56086431556 

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

               parametersValues         SE       RSE
μ_V                    0.740000 0.04772793  6.449720
μ_Cl                   0.280000 0.02392109  8.543246
μ_kout                 6.140000 1.07624035 17.528345
μ_Imax                 0.760000 0.09133501 12.017765
μ_IC50                 9.220000 1.03216841 11.194885
μ_gamma                2.770000 1.10845621 40.016470
ω²_V                   0.099856 0.03224496 32.291455
ω²_Cl                  0.207936 0.05622909 27.041537
ω²_kout                0.896809 0.23569615 26.281644
ω²_Imax                0.192721 0.08998922 46.694038
ω²_IC50                0.204304 0.09353945 45.784443
ω²_gamma               3.101121 1.07457623 34.651219
σ_slope_RespPK         0.210000 0.01908444  9.087828
σ_inter_RespPD         9.600000 1.69963286 17.704509
