Structural model: one-compartment, single bolus IV dose, parameterized using CL driving an EMAX model with a direct effect.

This is a structural model function that encodes the model described above. The function is suitable for input to the create.poped.database function using the ff_file argument.

ff.PKPD.1.comp.sd.CL.emax(model_switch, xt, parameters, poped.db)

Arguments

model_switch	a vector of values, the same size as `xt`, identifying which model response should be computed for the corresponding xt value. Used for multiple response models.
xt	a vector of independent variable values (often time).
parameters	A named list of parameter values.
poped.db	a poped database. This can be used to extract information that may be needed in the model file.

Value

A list consisting of:

y the values of the model at the specified points.
poped.db A (potentially modified) poped database.

Examples


library(PopED)

## find the parameters that are needed to define from the structural model
ff.PKPD.1.comp.sd.CL.emax
#> function (model_switch, xt, parameters, poped.db) 
#> {
#>     with(as.list(parameters), {
#>         y = xt
#>         MS <- model_switch
#>         CONC = DOSE/V * exp(-CL/V * xt)
#>         EFF = E0 + CONC * EMAX/(EC50 + CONC)
#>         y[MS == 1] = CONC[MS == 1]
#>         y[MS == 2] = EFF[MS == 2]
#>         return(list(y = y, poped.db = poped.db))
#>     })
#> }
#> <bytecode: 0x7fe1fd8e6ea8>
#> <environment: namespace:PopED>

## -- parameter definition function 
## -- names match parameters in function ff
sfg <- function(x,a,bpop,b,bocc){
  ## -- parameter definition function
  parameters=c( 
    CL=bpop[1]*exp(b[1])  ,
    V=bpop[2]*exp(b[2])  ,
    E0=bpop[3]*exp(b[3])  ,
    EMAX=bpop[4]*exp(b[4])  ,
    EC50=bpop[5]*exp(b[5])  ,
    DOSE=a[1]
  )
  return( parameters ) 
}

feps <- function(model_switch,xt,parameters,epsi,poped.db){
  ## -- Residual Error function
  ## -- Proportional PK + additive PD
  returnArgs <- do.call(poped.db$model$ff_pointer,list(model_switch,xt,parameters,poped.db)) 
  y <- returnArgs[[1]]
  poped.db <- returnArgs[[2]]
  
  MS <- model_switch
  
  prop.err <- y*(1+epsi[,1])
  add.err <- y+epsi[,2]
  
  y[MS==1] = prop.err[MS==1]
  y[MS==2] = add.err[MS==2]
  
  return(list( y= y,poped.db =poped.db )) 
}

## -- Define initial design  and design space
poped.db <- create.poped.database(ff_fun=ff.PKPD.1.comp.sd.CL.emax,
                                  fError_fun=feps,
                                  fg_fun=sfg,
                                  groupsize=20,
                                  m=3,
                                  sigma=diag(c(0.15,0.15)),
                                  bpop=c(CL=0.5,V=0.2,E0=1,EMAX=1,EC50=1),  
                                  d=c(CL=0.01,V=0.01,E0=0.01,EMAX=0.01,EC50=0.01), 
                                  xt=c( 0.33,0.66,0.9,5,0.1,1,2,5),
                                  model_switch=c( 1,1,1,1,2,2,2,2),
                                  minxt=0,
                                  maxxt=5,
                                  a=rbind(2.75,5,10),
                                  bUseGrouped_xt=1,
                                  maxa=10,
                                  mina=0.1)


##  create plot of model without variability 
plot_model_prediction(poped.db,facet_scales="free")

## evaluate initial design
FIM <- evaluate.fim(poped.db) 
FIM
#>               [,1]         [,2]      [,3]       [,4]       [,5]         [,6]
#>  [1,]  13423.83149 -26148.43438 -104.9746  -55.87794   20.58619 0.000000e+00
#>  [2,] -26148.43438  70314.08833 -137.2793 -103.59890   26.32348 0.000000e+00
#>  [3,]   -104.97460   -137.27932 1209.7986  516.06655 -116.00915 0.000000e+00
#>  [4,]    -55.87794   -103.59890  516.0666  449.35861  -62.47406 0.000000e+00
#>  [5,]     20.58619     26.32348 -116.0092  -62.47406   22.73598 0.000000e+00
#>  [6,]      0.00000      0.00000    0.0000    0.00000    0.00000 9.385378e+04
#>  [7,]      0.00000      0.00000    0.0000    0.00000    0.00000 5.697839e+04
#>  [8,]      0.00000      0.00000    0.0000    0.00000    0.00000 2.298710e+01
#>  [9,]      0.00000      0.00000    0.0000    0.00000    0.00000 6.524561e+00
#> [10,]      0.00000      0.00000    0.0000    0.00000    0.00000 8.880407e-01
#> [11,]      0.00000      0.00000    0.0000    0.00000    0.00000 1.115568e+03
#> [12,]      0.00000      0.00000    0.0000    0.00000    0.00000 1.345372e+01
#>               [,7]         [,8]         [,9]       [,10]        [,11]
#>  [1,] 0.000000e+00     0.000000    0.0000000   0.0000000    0.0000000
#>  [2,] 0.000000e+00     0.000000    0.0000000   0.0000000    0.0000000
#>  [3,] 0.000000e+00     0.000000    0.0000000   0.0000000    0.0000000
#>  [4,] 0.000000e+00     0.000000    0.0000000   0.0000000    0.0000000
#>  [5,] 0.000000e+00     0.000000    0.0000000   0.0000000    0.0000000
#>  [6,] 5.697839e+04    22.987097    6.5245606   0.8880407 1115.5680152
#>  [7,] 6.592095e+04     6.586597    3.6779636   0.2558559 1176.6041001
#>  [8,] 6.586597e+00 12197.738218 2243.7358555 112.3394149    4.8902658
#>  [9,] 3.677964e+00  2243.735855 1714.4795989  32.6395909    0.5891989
#> [10,] 2.558559e-01   112.339415   32.6395909   4.3373414    0.1964359
#> [11,] 1.176604e+03     4.890266    0.5891989   0.1964359 3811.1481605
#> [12,] 4.616968e+00  3055.546022 1230.5356715  65.5594938    3.8335502
#>             [,12]
#>  [1,]    0.000000
#>  [2,]    0.000000
#>  [3,]    0.000000
#>  [4,]    0.000000
#>  [5,]    0.000000
#>  [6,]   13.453723
#>  [7,]    4.616968
#>  [8,] 3055.546022
#>  [9,] 1230.535671
#> [10,]   65.559494
#> [11,]    3.833550
#> [12,] 4658.810828
det(FIM)
#> [1] 1.421054e+39
get_rse(FIM,poped.db)
#>          CL           V          E0        EMAX        EC50        d_CL 
#>    3.306524    3.610227    4.575451    6.825531   30.397923   47.350220 
#>         d_V        d_E0      d_EMAX      d_EC50  SIGMA[1,1]  SIGMA[2,2] 
#>   56.556024  113.036005  291.542904 5854.936456   10.829134   11.705173

Structural model: one-compartment, single bolus IV dose, parameterized using CL driving an EMAX model with a direct effect.

Arguments

Value

See also

Examples