suppressPackageStartupMessages({
  library(shiny)
  library(bslib)
  library(mrgsolve)
  library(dplyr)
  library(ggplot2)
})

model_code <- '
$PARAM @annotated
WT          : 22.8   : Body weight (kg)
ALT         : 26.5   : Alanine aminotransferase (IU/L)
GENO        : 0      : CYP2C19 genotype (0 = EM, 1 = HEM/PM)
CL_EMKG     : 0.582  : Clearance in EMs at reference ALT (L/h/kg)
HEM_DROP    : 0.355  : Fractional clearance reduction in HEM/PM
ALT_THETA   : -0.0931: ALT effect exponent on clearance
ALT_REF     : 26.5   : Reference ALT (IU/L)
KM_MG_L     : 3.03   : Michaelis-Menten constant (mg/L)
VC_KG       : 0.807  : Central volume (L/kg)
Q_KG        : 0.609  : Intercompartmental clearance (L/h/kg)
VP_KG       : 2.17   : Peripheral volume (L/kg)
KA          : 0.849  : Absorption rate constant (1/h)
F1          : 0.446  : Oral bioavailability

$CMT @annotated
DEPOT  : Oral depot (mg)
CENT   : Central compartment (mg)
PERIPH : Peripheral compartment (mg)
AUC    : Area under the concentration-time curve (mg*h/L)

$MAIN
double cl_factor = pow(ALT / ALT_REF, ALT_THETA);
double geno_factor = (GENO > 0.5) ? (1.0 - HEM_DROP) : 1.0;
double CLi = CL_EMKG * cl_factor * geno_factor * WT;
double VCi = VC_KG * WT;
double Qi = Q_KG * WT;
double VPi = VP_KG * WT;
double VMAX = CLi * KM_MG_L;
double K12 = Qi / VCi;
double K21 = Qi / VPi;
F_DEPOT = F1;

$ODE
double CP = CENT / VCi;
double ELIM = (CP > 0.0) ? (VMAX * CP / (KM_MG_L + CP)) : 0.0;
dxdt_DEPOT = -KA * DEPOT;
dxdt_CENT = KA * DEPOT - ELIM - K12 * CENT + K21 * PERIPH;
dxdt_PERIPH = K12 * CENT - K21 * PERIPH;
dxdt_AUC = CP;

$TABLE
double CP_MG_L = CENT / VCi;
double AUCOUT = AUC;
double CL_L_H = CLi;
double VMAX_MG_H = VMAX;
double VC_L = VCi;
double VP_L = VPi;
double Q_L_H = Qi;

$CAPTURE CP_MG_L AUCOUT CL_L_H VMAX_MG_H VC_L VP_L Q_L_H
'

mod <- mcode("pkpd_app_348_voriconazole", model_code)

app_theme <- bs_theme(
  version = 5,
  bootswatch = "flatly",
  primary = "#8b5cf6"
) |> bs_add_rules("
  .metric-card {
    background: #f8f9fa;
    border-radius: 8px;
    padding: 15px;
    margin: 5px;
    text-align: center;
    border: 1px solid #dee2e6;
    min-height: 108px;
  }
  .metric-value {
    font-size: 24px;
    font-weight: bold;
    color: #2c3e50;
  }
  .metric-label {
    font-size: 12px;
    color: #7f8c8d;
    margin-top: 4px;
  }
  .metric-subtext {
    font-size: 11px;
    color: #6c757d;
    margin-top: 6px;
  }
  .metric-success .metric-value { color: #10b981; }
  .metric-warning .metric-value { color: #f59e0b; }
  .metric-primary .metric-value { color: #8b5cf6; }
  .metric-info .metric-value { color: #0dcaf0; }
  .info-box {
    background: #f8f9ff;
    border: 1px solid #d8ddff;
    border-radius: 8px;
    padding: 12px 14px;
    margin-top: 10px;
    font-size: 13px;
  }
  .ref-box {
    background: #f0f4ff;
    border-left: 4px solid #8b5cf6;
    padding: 12px 16px;
    border-radius: 4px;
    margin-top: 10px;
    font-size: 13px;
  }
")

trap_auc <- function(time, conc) {
  if (length(time) < 2) {
    return(NA_real_)
  }
  sum(diff(time) * (head(conc, -1) + tail(conc, -1)) / 2)
}

calc_linear_half_life <- function(weight, alt, genotype) {
  cl_per_kg <- 0.582 * (alt / 26.5)^(-0.0931)
  if (identical(genotype, "HEM/PM")) {
    cl_per_kg <- cl_per_kg * (1 - 0.355)
  }
  cl <- cl_per_kg * weight
  vc <- 0.807 * weight
  q <- 0.609 * weight
  vp <- 2.17 * weight
  k10 <- cl / vc
  k12 <- q / vc
  k21 <- q / vp
  disc <- (k10 + k12 + k21)^2 - 4 * k21 * k10
  beta <- 0.5 * ((k10 + k12 + k21) - sqrt(max(disc, 0)))
  log(2) / beta
}

preset_values <- function(preset) {
  switch(
    preset,
    "Recommended IV: 7 mg/kg BID" = list(
      route = "iv",
      oral_mode = "fixed",
      iv_dose_mgkg = 7,
      oral_dose_mg = 200,
      oral_dose_mgkg = 6,
      interval_h = 12,
      infusion_h = 1.5
    ),
    "Recommended oral: 200 mg BID" = list(
      route = "oral",
      oral_mode = "fixed",
      iv_dose_mgkg = 7,
      oral_dose_mg = 200,
      oral_dose_mgkg = 6,
      interval_h = 12,
      infusion_h = 1.5
    ),
    "Study IV: 8 mg/kg BID" = list(
      route = "iv",
      oral_mode = "fixed",
      iv_dose_mgkg = 8,
      oral_dose_mg = 200,
      oral_dose_mgkg = 6,
      interval_h = 12,
      infusion_h = 1.5
    ),
    "Study oral: 4 mg/kg BID" = list(
      route = "oral",
      oral_mode = "mgkg",
      iv_dose_mgkg = 7,
      oral_dose_mg = 200,
      oral_dose_mgkg = 4,
      interval_h = 12,
      infusion_h = 1.5
    ),
    "Study oral: 6 mg/kg BID" = list(
      route = "oral",
      oral_mode = "mgkg",
      iv_dose_mgkg = 7,
      oral_dose_mg = 200,
      oral_dose_mgkg = 6,
      interval_h = 12,
      infusion_h = 1.5
    ),
    list(
      route = "iv",
      oral_mode = "fixed",
      iv_dose_mgkg = 7,
      oral_dose_mg = 200,
      oral_dose_mgkg = 6,
      interval_h = 12,
      infusion_h = 1.5
    )
  )
}

ui <- page_sidebar(
  title = "Voriconazole Pediatric PopPK Simulator",
  theme = app_theme,
  sidebar = sidebar(
    title = "Simulation Settings",
    width = 340,
    selectInput(
      "preset",
      "Paper preset",
      choices = c(
        "Custom",
        "Recommended IV: 7 mg/kg BID",
        "Recommended oral: 200 mg BID",
        "Study IV: 8 mg/kg BID",
        "Study oral: 4 mg/kg BID",
        "Study oral: 6 mg/kg BID"
      ),
      selected = "Recommended IV: 7 mg/kg BID"
    ),
    radioButtons(
      "route",
      "Route",
      choices = c("IV infusion" = "iv", "Oral" = "oral"),
      inline = TRUE
    ),
    conditionalPanel(
      "input.route === 'iv'",
      sliderInput("iv_dose_mgkg", "IV dose (mg/kg)", min = 3, max = 10, value = 7, step = 0.5),
      numericInput("infusion_h", "Infusion duration (h)", value = 1.5, min = 0.5, max = 4, step = 0.5)
    ),
    conditionalPanel(
      "input.route === 'oral'",
      radioButtons(
        "oral_mode",
        "Oral dose mode",
        choices = c("Fixed dose (mg)" = "fixed", "Weight-based (mg/kg)" = "mgkg"),
        inline = TRUE
      ),
      conditionalPanel(
        "input.oral_mode === 'fixed'",
        numericInput("oral_dose_mg", "Oral dose (mg)", value = 200, min = 50, max = 400, step = 25)
      ),
      conditionalPanel(
        "input.oral_mode === 'mgkg'",
        sliderInput("oral_dose_mgkg", "Oral dose (mg/kg)", min = 3, max = 12, value = 6, step = 0.5)
      )
    ),
    numericInput("interval_h", "Dosing interval (h)", value = 12, min = 8, max = 24, step = 1),
    numericInput("duration_days", "Simulation duration (days)", value = 14, min = 2, max = 21, step = 1),
    hr(),
    h6("Patient characteristics"),
    sliderInput("wt", "Body weight (kg)", min = 10, max = 55, value = 22.8, step = 0.5),
    selectInput(
      "genotype",
      "CYP2C19 genotype group",
      choices = c("Extensive metabolizer (EM)" = "EM", "Heterozygous/poor metabolizer (HEM/PM)" = "HEM/PM"),
      selected = "EM"
    ),
    numericInput("alt", "ALT (IU/L)", value = 26.5, min = 5, max = 300, step = 1),
    hr(),
    checkboxInput("log_scale", "Log scale", value = FALSE),
    div(
      class = "info-box",
      tags$strong("Paper recommendation:"),
      tags$div("7 mg/kg BID IV or 200 mg BID oral, without loading doses."),
      tags$div(style = "margin-top: 6px;", "Model uses the published final PopPK parameterization from Karlsson et al. 2009.")
    )
  ),
  layout_column_wrap(
    width = 1 / 4,
    fill = FALSE,
    div(
      class = "metric-card metric-success",
      div(class = "metric-value", textOutput("cmax")),
      div(class = "metric-label", "Cmax (mg/L)"),
      div(class = "metric-subtext", textOutput("dose_summary"))
    ),
    div(
      class = "metric-card metric-warning",
      div(class = "metric-value", textOutput("ctrough")),
      div(class = "metric-label", "Ctrough (mg/L)"),
      div(class = "metric-subtext", "End of final dosing interval")
    ),
    div(
      class = "metric-card metric-primary",
      div(class = "metric-value", textOutput("auc")),
      div(class = "metric-label", "AUC0-tau (mg*h/L)"),
      div(class = "metric-subtext", "Final dosing interval")
    ),
    div(
      class = "metric-card metric-info",
      div(class = "metric-value", textOutput("thalf")),
      div(class = "metric-label", "Approx. terminal t1/2 (h)"),
      div(class = "metric-subtext", "Linearized around low concentrations")
    )
  ),
  navset_card_underline(
    title = "Voriconazole Pediatric PopPK Simulator",
    nav_panel(
      "Simulation",
      card(
        full_screen = TRUE,
        plotOutput("pk_plot", height = "500px")
      )
    ),
    nav_panel(
      "Model Information",
      div(
        class = "info-box",
        tags$h5("Published structural model"),
        tags$ul(
          tags$li("Two-compartment disposition with Michaelis-Menten elimination."),
          tags$li("First-order oral absorption with no lag time."),
          tags$li("Weight scales CL, Vc, Q, and Vp linearly."),
          tags$li("Published final model covariates: CYP2C19 genotype group and ALT on clearance.")
        ),
        tags$h5("Final model parameters"),
        tags$ul(
          tags$li("Km = 3,030 ng/mL (3.03 mg/L)"),
          tags$li("Vc = 0.807 L/kg, Q = 0.609 L/h/kg, Vp = 2.17 L/kg"),
          tags$li("Ka = 0.849 h^-1, oral bioavailability = 44.6%"),
          tags$li("CL in EMs = 0.582 L/h/kg at ALT reference 26.5 IU/L"),
          tags$li("HEM/PM clearance reduction = 35.5%"),
          tags$li("ALT exponent on clearance = -0.0931")
        ),
        tags$h5("Implementation notes"),
        tags$ul(
          tags$li("The CYP2C9 inhibitor effect reported in the paper's alternative final model is intentionally excluded here."),
          tags$li("This simulator focuses on the typical-subject final model used for the manuscript's dose recommendation."),
          tags$li("Use the presets to reproduce the paper's recommended IV and oral maintenance regimens.")
        )
      )
    ),
    nav_panel(
      "References",
      div(
        class = "ref-box",
        tags$h5("Primary reference"),
        tags$ol(
          tags$li(
            "Karlsson MO, Lutsar I, Milligan PA. Population Pharmacokinetic Analysis of Voriconazole Plasma Concentration Data from Pediatric Studies. Antimicrob Agents Chemother. 2009;53(3):935-944. doi:10.1128/AAC.00751-08."
          )
        ),
        tags$h5("Clinical context from the manuscript"),
        tags$ul(
          tags$li("Population: pediatric patients 2 to <12 years of age."),
          tags$li("Recommended maintenance regimens: 7 mg/kg BID IV or 200 mg BID oral."),
          tags$li("No loading dose or baseline-covariate dose adjustment recommended by the paper.")
        )
      )
    )
  ),
  div(
    style = "text-align: center; padding: 20px; margin-top: 30px; border-top: 1px solid #e9ecef; color: #6c757d; font-size: 12px;",
    "Powered by ",
    tags$a(
      href = "https://www.pkpdbuilder.com",
      target = "_blank",
      style = "color: #8b5cf6; font-weight: 500;",
      "PKPDBuilder.com"
    ),
    " • Built by Sunny (Husain Attarwala's AI Assistant)", br(),
    tags$span(
      style = "font-size: 10px;",
      "For research and educational purposes only. Not for clinical decision-making."
    )
  )
)

server <- function(input, output, session) {
  observeEvent(input$preset, {
    if (identical(input$preset, "Custom")) {
      return()
    }
    vals <- preset_values(input$preset)
    updateRadioButtons(session, "route", selected = vals$route)
    updateRadioButtons(session, "oral_mode", selected = vals$oral_mode)
    updateSliderInput(session, "iv_dose_mgkg", value = vals$iv_dose_mgkg)
    updateNumericInput(session, "oral_dose_mg", value = vals$oral_dose_mg)
    updateSliderInput(session, "oral_dose_mgkg", value = vals$oral_dose_mgkg)
    updateNumericInput(session, "interval_h", value = vals$interval_h)
    updateNumericInput(session, "infusion_h", value = vals$infusion_h)
  }, ignoreInit = TRUE)

  dose_amount <- reactive({
    shiny::req(input$route)
    if (identical(input$route, "iv")) {
      input$iv_dose_mgkg * input$wt
    } else if (identical(input$oral_mode, "mgkg")) {
      input$oral_dose_mgkg * input$wt
    } else {
      input$oral_dose_mg
    }
  })

  regimen_label <- reactive({
    shiny::req(input$route)
    if (identical(input$route, "iv")) {
      sprintf("IV infusion %.1f mg/kg Q%sh", input$iv_dose_mgkg, input$interval_h)
    } else if (identical(input$oral_mode, "mgkg")) {
      sprintf("Oral %.1f mg/kg Q%sh", input$oral_dose_mgkg, input$interval_h)
    } else {
      sprintf("Oral %s mg Q%sh", format(round(input$oral_dose_mg, 1), trim = TRUE), input$interval_h)
    }
  })

  sim_data <- reactive({
    shiny::req(input$interval_h, input$duration_days, input$wt, input$alt)
    n_doses <- max(1L, as.integer(round(input$duration_days * 24 / input$interval_h)))
    end_time <- input$duration_days * 24
    genotype_flag <- if (identical(input$genotype, "HEM/PM")) 1 else 0

    ev_obj <- if (identical(input$route, "iv")) {
      shiny::req(input$infusion_h > 0)
      ev(
        amt = dose_amount(),
        cmt = 2,
        ii = input$interval_h,
        addl = n_doses - 1L,
        rate = dose_amount() / input$infusion_h
      )
    } else {
      ev(
        amt = dose_amount(),
        cmt = 1,
        ii = input$interval_h,
        addl = n_doses - 1L
      )
    }

    mod %>%
      param(WT = input$wt, ALT = input$alt, GENO = genotype_flag) %>%
      ev(ev_obj) %>%
      mrgsim(end = end_time, delta = 0.05) %>%
      as.data.frame() |>
      mutate(time_h = time)
  })

  interval_metrics <- reactive({
    data <- sim_data()
    last_start <- max(0, max(data$time_h, na.rm = TRUE) - input$interval_h)
    last_interval <- data |>
      dplyr::filter(time_h >= last_start, time_h <= max(time_h, na.rm = TRUE))

    list(
      cmax = max(last_interval$CP_MG_L, na.rm = TRUE),
      ctrough = dplyr::last(last_interval$CP_MG_L),
      auc = trap_auc(last_interval$time_h, last_interval$CP_MG_L)
    )
  })

  output$dose_summary <- renderText({
    sprintf("Dose = %.1f mg", dose_amount())
  })

  output$cmax <- renderText({
    sprintf("%.2f", interval_metrics()$cmax)
  })

  output$ctrough <- renderText({
    sprintf("%.2f", interval_metrics()$ctrough)
  })

  output$auc <- renderText({
    sprintf("%.1f", interval_metrics()$auc)
  })

  output$thalf <- renderText({
    sprintf("%.1f", calc_linear_half_life(input$wt, input$alt, input$genotype))
  })

  output$pk_plot <- renderPlot({
    data <- sim_data()
    plot_data <- if (isTRUE(input$log_scale)) {
      data |>
        dplyr::filter(CP_MG_L > 0)
    } else {
      data
    }

    plot_obj <- ggplot(plot_data, aes(x = time_h, y = CP_MG_L)) +
      geom_line(color = "#8b5cf6", linewidth = 0.9) +
      labs(
        title = regimen_label(),
        subtitle = "Final pediatric PopPK model from Karlsson et al. (2009)",
        x = "Time (hours)",
        y = "Voriconazole concentration (mg/L)"
      ) +
      theme_minimal(base_size = 14) +
      theme(
        plot.title = element_text(face = "bold"),
        plot.subtitle = element_text(color = "#6c757d")
      )

    if (isTRUE(input$log_scale)) {
      plot_obj <- plot_obj + scale_y_log10()
    }

    plot_obj
  })
}

shinyApp(ui = ui, server = server)