## Warfarin example from software comparison in:
## Nyberg et al., "Methods and software tools for design evaluation
## for population pharmacokinetics-pharmacodynamics studies",
## Br. J. Clin. Pharm., 2014.
library(PopED)
ff <- function(model_switch,xt,parameters,poped.db){
##-- Model: One comp first order absorption
with(as.list(parameters),{
y=xt
y=(DOSE*Favail*KA/(V*(KA-CL/V)))*(exp(-CL/V*xt)-exp(-KA*xt))
return(list(y=y,poped.db=poped.db))
})
}
sfg <- function(x,a,bpop,b,bocc){
## -- parameter definition function
parameters=c(CL=bpop[1]*exp(b[1]),
V=bpop[2]*exp(b[2]),
KA=bpop[3]*exp(b[3]),
Favail=bpop[4],
DOSE=a[1])
return(parameters)
}
feps <- function(model_switch,xt,parameters,epsi,poped.db){
## -- Residual Error function
## -- Proportional
returnArgs <- ff(model_switch,xt,parameters,poped.db)
y <- returnArgs[[1]]
poped.db <- returnArgs[[2]]
y = y*(1+epsi[,1])
return(list(y=y,poped.db=poped.db))
}
## -- Define initial design and design space
poped.db <- create.poped.database(ff_file="ff",
fg_file="sfg",
fError_file="feps",
bpop=c(CL=0.15, V=8, KA=1.0, Favail=1),
notfixed_bpop=c(1,1,1,0),
d=c(CL=0.07, V=0.02, KA=0.6),
sigma=0.01,
groupsize=32,
xt=c( 0.5,1,2,6,24,36,72,120),
minxt=0,
maxxt=120,
a=70)
## -- With covariances
poped.db_with <- create.poped.database(ff_file="ff",
fg_file="sfg",
fError_file="feps",
bpop=c(CL=0.15, V=8, KA=1.0, Favail=1),
notfixed_bpop=c(1,1,1,0),
d=c(CL=0.07, V=0.02, KA=0.6),
covd = c(.03,.1,.09),
sigma=0.01,
groupsize=32,
xt=c( 0.5,1,2,6,24,36,72,120),
minxt=0,
maxxt=120,
a=70)
# What do the covariances mean?
(IIV <- poped.db_with$parameters$param.pt.val$d)
cov2cor(IIV)
## create plot of model with variability
library(ggplot2)
p1 <- plot_model_prediction(poped.db,IPRED=T)+ylim(0,12)
p2 <- plot_model_prediction(poped.db_with,IPRED=T) +ylim(0,12)
gridExtra::grid.arrange(p1, p2, nrow = 1)
## evaluate initial design
evaluate_design(poped.db)
evaluate_design(poped.db_with)
## Evaluate with full FIM
evaluate_design(poped.db, fim.calc.type=0)
evaluate_design(poped.db_with, fim.calc.type=0)
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