library(posologyr)

mod_warfarin_nlmixr <- function() {
  ini({
    #Fixed effects: population estimates
    THETA_ktr=0.106
    THETA_ka=-0.087
    THETA_cl=-2.03
    THETA_v=2.07
    THETA_emax=3.4
    THETA_ec50=0.00724
    THETA_kout=-2.9
    THETA_e0=4.57

    #Random effects: inter-individual variability
    ETA_ktr ~ 1.024695
    ETA_ka ~ 0.9518403
    ETA_cl ~ 0.5300943
    ETA_v ~ 0.4785394
    ETA_emax ~ 0.7134424
    ETA_ec50 ~ 0.7204165
    ETA_kout ~ 0.3563706
    ETA_e0 ~ 0.2660827

    #Unexplained residual variability
    cp.sd <- 0.144
    cp.prop.sd <- 0.15
    pca.sd <- 3.91
  })
  model({
    #Individual model and covariates
    ktr <- exp(THETA_ktr + ETA_ktr)
    ka <- exp(THETA_ka + ETA_ka)
    cl <- exp(THETA_cl + ETA_cl)
    v <- exp(THETA_v + ETA_v)
    emax = expit(THETA_emax + ETA_emax)
    ec50 =  exp(THETA_ec50 + ETA_ec50)
    kout = exp(THETA_kout + ETA_kout)
    e0 = exp(THETA_e0 + ETA_e0)

    #Structural model defined using ordinary differential equations (ODE)
    DCP = center/v
    PD=1-emax*DCP/(ec50+DCP)

    effect(0) = e0
    kin = e0*kout

    d/dt(depot) = -ktr * depot
    d/dt(gut) =  ktr * depot -ka * gut
    d/dt(center) =  ka * gut - cl / v * center
    d/dt(effect) = kin*PD -kout*effect

    cp = center / v
    pca = effect

    #Model for unexplained residual variability
    cp ~ add(cp.sd) + prop(cp.prop.sd)
    pca ~ add(pca.sd)
  })
}

warf_01 <- data.frame(ID=1,
                      TIME=c(0.0,1.0,3.0,6.0,24.0,24.0,36.0,36.0,48.0,48.0,72.0,72.0,144.0),
                      DV=c(0.0,1.9,6.6,10.8,5.6,44.0,4.0,27.0,2.7,28.0,0.8,31.0,71.0),
                      DVID=c("cp","cp","cp","cp","cp","pca","cp","pca","cp","pca","cp","pca","pca"),
                      EVID=c(1,0,0,0,0,0,0,0,0,0,0,0,0),
                      AMT=c(100,0,0,0,0,0,0,0,0,0,0,0,0))


map_warf_01  <- poso_estim_map(warf_01,mod_warfarin_nlmixr)
#> ℹ parameter labels from comments are typically ignored in non-interactive mode
#> ℹ Need to run with the source intact to parse comments
#> using C compiler: ‘gcc (Ubuntu 11.4.0-1ubuntu1~22.04) 11.4.0’

plot(map_warf_01$model, "cp")

plot(map_warf_01$model, "pca")