DESCRIPTION:
Two compartment TMDD model for multiple doses into central compartment


[LONGITUDINAL]
input = {kel, kep, kon, kout, koff, ktp, kpt, Vc, R0}

PK:
; Dosemg: Dose injected into central compartment (mg/kg)
; MWlig=150000; molecular weight of ligand (Da) 
; (Dosemg*1e-3/MWlig)*1e9 ; Dose conversion (nmol/kg)

depot(target=L, p=100/15/Vc)  ; L is a concentration (nM)

EQUATION:
odeType = stiff

kin = kout*R0 ; Synthesis of receptor (nM/day)

;Initial Conditions
R_0 = R0

;Ordinary Differential Equations
ddt_L = -kel*L - kon*L*R + koff*P + ktp*Lt - kpt*L
ddt_R = kin - kout*R - kon*L*R + koff*P
ddt_P = kon*L*R - koff*P - kep*P
ddt_Lt= -ktp*Lt + kpt*L

ui <- shinyUI(fluidPage(
navbarPage("TMDD - Model 2",
tabPanel("Plot",
fluidRow(
column(2,
tabsetPanel(type='tabs',
tabPanel('param1',br(),
sliderInput("kel", label="kel",value=0.046,min=0.023,max=0.092,step=0.0046),
sliderInput("kep", label="kep",value=0.17,min=0.085,max=0.34,step=0.017),
sliderInput("kout", label="kout",value=17.3,min=8.65,max=34.6,step=1.73),
sliderInput("koff", label="koff",value=169,min=84.5,max=338,step=16.9),
br()
),
tabPanel('param2',br(),
sliderInput("kon", label="kon",value=30.2,min=15.1,max=60.4,step=3.02),
sliderInput("ktp", label="ktp",value=0.725,min=0.3625,max=1.45,step=0.0725),
sliderInput("kpt", label="kpt",value=0.902,min=0.451,max=1.804,step=0.0902),
sliderInput("R0", label="R0",value=0.00657,min=0.003285,max=0.01314,step=0.000657),
sliderInput("Vc", label="Vc",value=0.04,min=0.02,max=0.08,step=0.004),
br()
),
tabPanel('adm',br(),
sliderInput("tfd1", label="tfd",value=12,min=0,max=24,step=3),
sliderInput("nd1", label="nd",value=4,min=1,max=10,step=1),
sliderInput("ii1", label="ii",value=28,min=7,max=112,step=7),
sliderInput("amount1", label="amount",value=10,min=0,max=40,step=0.5),
br()
),
br()
)

),
column(2,
br(),
checkboxGroupInput("out1", label="plot 1", choices='L', selected='L'),

selectInput("x1", label="v.s.",c('time','L','R','P')),
hr(),
checkboxGroupInput("out2", label="plot 2", choices='R', selected='R'),

selectInput("x2", label="v.s.",c('time','L','R','P')),
hr(),
checkboxGroupInput("out3", label="plot 3", choices='P', selected='P'),

selectInput("x3", label="v.s.",c('time','L','R','P')),
hr()
),
column(8,br(),            
       plotOutput("plot"),
       br(),
       br(),
       br(),
       br(),
       br(),
       fluidRow(
         column(1),
         column(1,checkboxInput("boxref", label="ref.")),
         column(3,actionButton("butref", label = "Reset")),
         column(7,radioButtons("ilog", "scale", c("linear" = FALSE,"log  " = TRUE), inline=TRUE))
       )
)
)
),
tabPanel("Model", pre(includeText("model.txt"))),
tabPanel("ui.R", pre(includeText("ui.R"))),
tabPanel("server.R", pre(includeText("server.R")))
)
))

library("mlxR")
library("reshape")
library("gridExtra")
source("shinymlxTools.R")

out1 <- list(name='L', time=seq(0,360,by=1))
out2 <- list(name='R', time=seq(0,360,by=1))
out3 <- list(name='P', time=seq(0,360,by=1))
f  <- list(out1, out2, out3)
nf <- length(f)
info <- info_res(f)

server <- function(input, output) {
  ref <- reactive({
    input$butref
    p <- list(name  = c('kel', 'kep', 'kout', 'koff', 'kon', 'ktp', 'kpt', 'R0', 'Vc'),
              value = isolate(c(input$kel, input$kep, input$kout, input$koff, input$kon, input$ktp, input$kpt, input$R0, input$Vc)))
    t1 <- isolate(input$tfd1)
    t2 <- isolate(input$ii1)*(isolate(input$nd1)-1)+t1
    t.dose <- seq(t1,t2,by=isolate(input$ii1))
    adm <- list(time=t.dose, amount=isolate(input$amount1))
    r <- simulx( model     = 'model.txt',
                 treatment = adm,
                 parameter = p,
                 output    = f)

    ref <- merge_res(r,f)
    return(ref)
  })
  
  res <- reactive({
    p <- list(name  = c('kel', 'kep', 'kout', 'koff', 'kon', 'ktp', 'kpt', 'R0', 'Vc'),
              value = c(input$kel, input$kep, input$kout, input$koff, input$kon, input$ktp, input$kpt, input$R0, input$Vc))
    t1 <- input$tfd1
    t2 <- input$ii1*(input$nd1-1)+t1
    t.dose <- seq(t1,t2,by=input$ii1)
    adm <- list(time=t.dose, amount=input$amount1)                     
    r <- simulx( model     = 'model.txt',
                 treatment = adm,
                 parameter = p,
                 output    = f)
                     
    res <- merge_res(r,f)
    return(res)
  })  
  
  output$plot <- renderPlot({
    res=res()
   ref=ref()    
    gr.txt <- "grid.arrange("
    for (j in (1:length(f))){
      xj <- "time"
      fj <- f[[j]]
      name.fj <- fj$name

   eval(parse(text=paste0("inputyj=input$out",j)))  
  i.plot=FALSE
  if (!is.null(inputyj)){
    ij <- which(name.fj %in% inputyj)
    if (length(ij>0)){
      eval(parse(text=paste0("inputxj=input$x",j)))
      if (!is.null(inputxj))
        xj <- inputxj
    }
    i.plot=TRUE
  }
  else if (is.null(inputyj) & length(f)==1){
    ij=1
    i.plot=TRUE
  }
  if (i.plot){
    pl <- ggplotmlx()
    nfj <- length(name.fj)
    for (k in (1:nfj)){
      if (k %in% ij){
           if (input$boxref==TRUE){
      pj <- paste0('pl <- pl + geom_path(data=ref, aes(x=',xj,',y=',name.fj[k],'),colour="grey",size=0.75)')
      eval(parse(text=pj))
    }
   pj <- paste0('pl <- pl + geom_path(data=res, aes(x=',xj,',y=',name.fj[k],',colour="',info[[j]]$colour[k],'"),size=0.75)')
    eval(parse(text=pj))
      }  
    }
    pl <- pl + scale_colour_manual(values=info[[j]]$values, labels=info[[j]]$labels)
    print(pl)
    if (length(ij)>1){
      if (!is.null(input$legend) && input$legend==FALSE)
        pl <- pl + theme(legend.position="none")
      else
        pl <- pl + guides(colour=guide_legend(title=NULL)) + theme(legend.position=c(.9, .8))
      pl <- pl + ylab("")
    }else{
      pl <- pl + theme(legend.position="none")
    }
  
      if (input$ilog==TRUE)
       pl=pl + scale_y_log10()
    eval(parse(text=paste0("pl",j," <- pl")))
    gr.txt <- paste0(gr.txt,"pl",j,",")
  }
    }
    gr.txt <- paste0(gr.txt,"ncol=1)")
    eval(parse(text=gr.txt))
  }, height = 500)
}