library(shiny)
library(bslib)
library(mrgsolve)
library(dplyr)
library(ggplot2)

model_code <- '
$PARAM @annotated
CL : 0.0739 : Apparent clearance after separating F (L/day)
V  : 7.44   : Apparent volume after separating F (L)
KA : 0.542  : First-order absorption rate constant (1/day)
F1 : 0.70   : Subcutaneous bioavailability (fraction)

$CMT @annotated
DEPOT : Subcutaneous depot (mg)
CENT  : Central compartment (mg)

$MAIN
F_DEPOT = F1;

$ODE
dxdt_DEPOT = -KA * DEPOT;
dxdt_CENT  = KA * DEPOT - (CL / V) * CENT;

$TABLE
double CP = CENT / V;
double KEL = CL / V;
double THALF = log(2.0) / KEL;

$CAPTURE @annotated
CP    : Plasma concentration (mg/L; numerically equal to ug/mL)
KEL   : Elimination rate constant (1/day)
THALF : Terminal half-life (day)
'

mod <- mcode("orka002_hs_318", model_code, quiet = TRUE)

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;
    }
    .metric-value {
      font-size: 24px;
      font-weight: bold;
      color: #2c3e50;
    }
    .metric-label {
      font-size: 12px;
      color: #7f8c8d;
    }
    .metric-success .metric-value { color: #10b981; }
    .metric-warning .metric-value { color: #f59e0b; }
    .metric-primary .metric-value { color: #8b5cf6; }
    .metric-info .metric-value { color: #0dcaf0; }
    .ref-box {
      background: #f0f4ff;
      border-left: 4px solid #8b5cf6;
      padding: 12px 16px;
      border-radius: 4px;
      margin-top: 10px;
      font-size: 13px;
    }
    .small-note {
      color: #6c757d;
      font-size: 12px;
      margin-top: 8px;
    }
    .info-grid td {
      padding: 6px 10px;
      vertical-align: top;
      border-bottom: 1px solid #eef2f7;
    }
    .info-grid td:first-child {
      font-weight: 600;
      width: 230px;
    }
  ")

regimen_choices <- c(
  "Single 320 mg SC dose (PK reference)" = "single_320",
  "HS modeled regimen" = "hs_regimen",
  "Custom fixed-interval SC regimen" = "custom"
)

build_regimen_schedule <- function(regimen, duration_weeks, custom_dose = 320, custom_interval = 12) {
  duration_days <- duration_weeks * 7

  if (regimen == "single_320") {
    times <- 0
    dose <- 320
    metric_interval <- 84
    label <- "Single 320 mg SC dose"
  } else if (regimen == "hs_regimen") {
    induction <- c(0, 4, 8, 12) * 7
    maintenance <- seq(24, ceiling(duration_weeks) + 12, by = 12) * 7
    times <- sort(unique(c(induction, maintenance)))
    times <- times[times <= duration_days]
    if (length(times) == 0) {
      times <- 0
    }
    dose <- 320
    metric_interval <- if (length(times) > 1 && max(times) >= 24 * 7) 84 else 28
    label <- "HS regimen: 320 mg at Weeks 0, 4, 8, and 12, then every 12 weeks"
  } else {
    interval_days <- custom_interval * 7
    times <- seq(0, duration_days, by = interval_days)
    dose <- custom_dose
    metric_interval <- interval_days
    label <- paste0("Custom SC regimen: ", custom_dose, " mg every ", custom_interval, " weeks")
  }

  list(
    times = times,
    dose = dose,
    metric_interval = metric_interval,
    label = label
  )
}

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

ui <- page_sidebar(
  title = "ORKA-002 HS PK Simulator",
  theme = app_theme,
  sidebar = sidebar(
    title = "Simulation Settings",
    width = 340,
    selectInput("regimen", "Regimen", choices = regimen_choices, selected = "hs_regimen"),
    conditionalPanel(
      condition = "input.regimen == 'custom'",
      sliderInput("custom_dose", "Dose (mg)", min = 80, max = 640, value = 320, step = 20),
      sliderInput("custom_interval", "Interval (weeks)", min = 2, max = 24, value = 12, step = 1)
    ),
    numericInput("duration_weeks", "Simulation duration (weeks)", value = 72, min = 12, max = 156, step = 4),
    checkboxInput("log_scale", "Log scale (Y-axis)", value = FALSE),
    div(
      class = "small-note",
      "This simulator uses the hidradenitis suppurativa-adjusted ORKA-002 PK summary values provided in the uploaded manuscript."
    )
  ),
  layout_column_wrap(
    width = 1 / 4,
    fill = FALSE,
    div(class = "metric-card metric-success",
        div(class = "metric-value", textOutput("cmax")),
        div(class = "metric-label", "Last-interval Cmax (ug/mL)")),
    div(class = "metric-card metric-warning",
        div(class = "metric-value", textOutput("ctrough")),
        div(class = "metric-label", "Last-interval Ctrough (ug/mL)")),
    div(class = "metric-card metric-primary",
        div(class = "metric-value", textOutput("auc")),
        div(class = "metric-label", "Last-interval AUC (ug*day/mL)")),
    div(class = "metric-card metric-info",
        div(class = "metric-value", textOutput("thalf")),
        div(class = "metric-label", "Terminal t1/2 (days)"))
  ),
  card(
    card_header("Concentration-Time Profile"),
    full_screen = TRUE,
    plotOutput("pkPlot", height = "500px"),
    div(class = "small-note", textOutput("plot_note"))
  ),
  navset_card_underline(
    title = "Drug Information",
    nav_panel("Model Information", uiOutput("model_info")),
    nav_panel("References", uiOutput("references"))
  ),
  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) {
  sim_bundle <- reactive({
    schedule <- build_regimen_schedule(
      regimen = input$regimen,
      duration_weeks = input$duration_weeks,
      custom_dose = input$custom_dose,
      custom_interval = input$custom_interval
    )

    event_df <- data.frame(
      ID = 1,
      time = schedule$times,
      amt = schedule$dose,
      cmt = 1,
      evid = 1
    )

    sim_end <- max(input$duration_weeks * 7, max(schedule$times) + schedule$metric_interval)

    sim <- mod %>%
      data_set(event_df) %>%
      mrgsim(end = sim_end, delta = 0.25) %>%
      as.data.frame() |>
      mutate(
        time_days = time,
        time_weeks = time / 7
      )

    last_dose_time <- max(schedule$times)
    metric_end <- last_dose_time + schedule$metric_interval
    interval_data <- sim |>
      dplyr::filter(time_days >= last_dose_time, time_days <= metric_end)

    list(
      sim = sim,
      schedule = schedule,
      plot_end = input$duration_weeks * 7,
      interval_data = interval_data,
      last_dose_time = last_dose_time,
      metric_end = metric_end
    )
  })

  output$cmax <- renderText({
    d <- sim_bundle()$interval_data
    shiny::req(nrow(d) > 0)
    sprintf("%.1f", max(d$CP, na.rm = TRUE))
  })

  output$ctrough <- renderText({
    d <- sim_bundle()$interval_data
    shiny::req(nrow(d) > 0)
    sprintf("%.1f", d$CP[nrow(d)])
  })

  output$auc <- renderText({
    d <- sim_bundle()$interval_data
    shiny::req(nrow(d) > 1)
    sprintf("%.1f", trap_auc(d$time_days, d$CP))
  })

  output$thalf <- renderText({
    sprintf("%.1f", log(2) * 7.44 / 0.0739)
  })

  output$plot_note <- renderText({
    paste0(
      "Metrics are calculated over the final dosing interval after the last simulated dose. Current regimen: ",
      sim_bundle()$schedule$label
    )
  })

  output$pkPlot <- renderPlot({
    bundle <- sim_bundle()
    d <- bundle$sim |>
      dplyr::filter(time_days <= bundle$plot_end)
    shiny::req(nrow(d) > 0)

    d_plot <- if (input$log_scale) {
      d |>
        dplyr::filter(CP > 0.001)
    } else {
      d
    }
    shiny::req(nrow(d_plot) > 0)

    dose_df <- data.frame(time_weeks = bundle$schedule$times / 7)

    p <- ggplot(d_plot, aes(x = time_weeks, y = CP)) +
      geom_vline(data = dose_df, aes(xintercept = time_weeks), color = "#cbd5e1", linetype = "dashed", linewidth = 0.4) +
      geom_line(color = "#8b5cf6", linewidth = 1) +
      labs(
        x = "Time (weeks)",
        y = "Plasma concentration (ug/mL)",
        title = "ORKA-002 hidradenitis suppurativa concentration-time profile"
      ) +
      theme_minimal(base_size = 14)

    if (input$regimen == "single_320") {
      cmax_ref <- max(bundle$interval_data$CP, na.rm = TRUE)
      p <- p +
        geom_hline(yintercept = cmax_ref, color = "#10b981", linetype = "dotted", linewidth = 0.8) +
        annotate(
          "text",
          x = 2,
          y = cmax_ref * 1.07,
          label = paste0("Model-predicted single-dose Cmax ~", sprintf("%.1f", cmax_ref), " ug/mL"),
          color = "#10b981",
          hjust = 0,
          size = 3.4
        )
    }

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

    p
  })

  output$model_info <- renderUI({
    bundle <- sim_bundle()
    div(
      tags$h4("ORKA-002 — pragmatic HS-adjusted SC biologic PK model"),
      tags$p("This simulator implements the uploaded ORKA-002 manuscript summary as a one-compartment subcutaneous biologic model with first-order absorption."),
      tags$table(
        class = "info-grid",
        tags$tr(tags$td("Drug"), tags$td("ORKA-002")),
        tags$tr(tags$td("Class"), tags$td("Humanized IgG1 monoclonal antibody against IL-17A / IL-17F with YTE half-life extension")),
        tags$tr(tags$td("Route"), tags$td("Subcutaneous")),
        tags$tr(tags$td("Use case"), tags$td("Hidradenitis suppurativa exposure simulation")),
        tags$tr(tags$td("Model structure"), tags$td("1-compartment SC absorption model")),
        tags$tr(tags$td("Bioavailability (F)"), tags$td("0.70")),
        tags$tr(tags$td("Absorption rate (Ka)"), tags$td("0.542 day^-1")),
        tags$tr(tags$td("Effective volume (V)"), tags$td("7.44 L")),
        tags$tr(tags$td("Effective clearance (CL)"), tags$td("0.0739 L/day")),
        tags$tr(tags$td("Elimination rate constant"), tags$td("0.00993 day^-1")),
        tags$tr(tags$td("Terminal half-life"), tags$td("~69.8 days")),
        tags$tr(tags$td("Modeled regimen"), tags$td(bundle$schedule$label))
      ),
      tags$div(
        class = "ref-box",
        tags$strong("Calibration notes"),
        tags$ul(
          tags$li("The uploaded summary states that the model was calibrated to a Phase 1 healthy-volunteer PK curve and a sponsor-reported half-life of 75 to 80 days."),
          tags$li("The HS version applies a disease-state exposure adjustment with higher clearance and higher volume, producing an HS-adjusted terminal half-life of about 70 days."),
          tags$li("This is a pragmatic exposure simulator intended for exploratory PK visualization, not a proprietary full population PK reconstruction.")
        )
      )
    )
  })

  output$references <- renderUI({
    div(
      class = "ref-box",
      tags$h5("Key sources"),
      tags$ol(
        tags$li("Uploaded manuscript summary: ORKA-002 population PK summary for hidradenitis suppurativa (project file ORKA-002_HS.pdf)."),
        tags$li(
          tags$a(href = "https://orukatx.com/our-pipeline/", target = "_blank", "Oruka Therapeutics pipeline page"),
          " — confirms ORKA-002 as a half-life-extended IL-17A/F monoclonal antibody under Phase 1 development."
        ),
        tags$li(
          tags$a(href = "https://ir.orukatx.com/news-releases/news-release-details/oruka-therapeutics-announces-first-participants-dosed-phase-1-0", target = "_blank", "Oruka Phase 1 announcement"),
          " — supports the clinical development context and extended-dosing positioning."
        )
      ),
      tags$h5("What this app covers"),
      tags$ul(
        tags$li("Subcutaneous ORKA-002 exposure under the manuscript's HS-adjusted regimen and custom fixed-interval regimens."),
        tags$li("Relative accumulation and washout across long-interval dosing schedules."),
        tags$li("Exploratory PK simulation only; no direct efficacy or safety threshold modeling.")
      )
    )
  })
}

shinyApp(ui = ui, server = server)