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

model_code <- '
$PARAM @annotated
CL         : 0.87        : Clearance (L/day)
V1         : 12.64       : Central volume (L)
V2         : 2.61        : Peripheral volume (L)
Q          : 0.21        : Intercompartmental clearance (L/day)
KA         : 0.48        : First-order absorption rate constant (1/day)
F1         : 0.45        : SC bioavailability
WT         : 77.4        : Body weight (kg)
REFWT      : 77.4        : Reference body weight (kg)
ALLOM      : 0           : Apply exploratory allometry (0/1)
EXP_CL     : 0.75        : Allometric exponent for CL
EXP_V      : 1.0         : Allometric exponent for volume
MW_TOZO    : 145500      : Molecular weight (g/mol)
KEL_IL33   : 4.83        : IL-33 elimination rate (1/day)
KON_TOZO   : 68.85       : IL-33-tozorakimab association constant (1/nM/day)
KD_TOZO    : 0.00003     : IL-33-tozorakimab dissociation constant (nM)
KEL_SST2   : 0.069       : sST2 elimination rate (1/day)
KON_SST2   : 91.38       : IL-33-sST2 association constant (1/nM/day)
KD_SST2    : 0.0006      : IL-33-sST2 dissociation constant (nM)
BL_COMPLEX : 0.00047     : Baseline IL-33/sST2 complex (nM)
BL_SST2    : 0.20        : Baseline free sST2 (nM)
EC50_TE    : 0.0111      : Published Figure 5-calibrated EC50 for systemic TE (ug/mL)
HILL_TE    : 0.96        : Published Figure 5-calibrated Hill coefficient for systemic TE

$CMT @annotated
DEPOT    : SC depot (mg)
CENT     : Central compartment (mg)
PERIPH   : Peripheral compartment (mg)
IL33FREE : Free IL-33 in central compartment (nM)
SST2FREE : Free sST2 in central compartment (nM)
IL33TOZO : IL-33/tozorakimab complex (nM)
IL33SST2 : IL-33/sST2 complex (nM)

$MAIN
if(NEWIND <= 1) {
  IL33FREE_0 = 1.41e-06;
  SST2FREE_0 = 0.20;
  IL33TOZO_0 = 0.0;
  IL33SST2_0 = 0.00047;
}
F_DEPOT = F1;

$ODE
double nm_per_mgL_ode = 1.0e6 / MW_TOZO;
double mgL_per_nM_ode = MW_TOZO / 1.0e6;
double scale_cl_ode = ALLOM > 0.5 ? pow(WT / REFWT, EXP_CL) : 1.0;
double scale_v_ode = ALLOM > 0.5 ? pow(WT / REFWT, EXP_V) : 1.0;
double CLi_ode = CL * scale_cl_ode;
double V1i_ode = V1 * scale_v_ode;
double V2i_ode = V2 * scale_v_ode;
double KOFF_TOZO_ode = KON_TOZO * KD_TOZO;
double KOFF_SST2_ode = KON_SST2 * KD_SST2;
double BL_IL33_ode = BL_COMPLEX * KD_SST2 / BL_SST2;
double KIN_IL33_ode = KEL_IL33 * BL_IL33_ode + KON_SST2 * BL_IL33_ode * BL_SST2 - KOFF_SST2_ode * BL_COMPLEX;
double KIN_SST2_ode = KEL_SST2 * BL_SST2 + KON_SST2 * BL_IL33_ode * BL_SST2 - KOFF_SST2_ode * BL_COMPLEX;
double TOZO_FREE_NM_ode = (CENT / V1i_ode) * nm_per_mgL_ode;
double bind_tozo_nM_ode = KON_TOZO * TOZO_FREE_NM_ode * IL33FREE - KOFF_TOZO_ode * IL33TOZO;
double bind_sst2_nM_ode = KON_SST2 * IL33FREE * SST2FREE - KOFF_SST2_ode * IL33SST2;
double bind_tozo_mg_ode = bind_tozo_nM_ode * mgL_per_nM_ode * V1i_ode;

dxdt_DEPOT = -KA * DEPOT;
dxdt_CENT = KA * DEPOT - (CLi_ode / V1i_ode + Q / V1i_ode) * CENT + (Q / V2i_ode) * PERIPH - bind_tozo_mg_ode;
dxdt_PERIPH = (Q / V1i_ode) * CENT - (Q / V2i_ode) * PERIPH;
dxdt_IL33FREE = KIN_IL33_ode - KEL_IL33 * IL33FREE - bind_tozo_nM_ode - bind_sst2_nM_ode;
dxdt_SST2FREE = KIN_SST2_ode - KEL_SST2 * SST2FREE - bind_sst2_nM_ode;
dxdt_IL33TOZO = bind_tozo_nM_ode - (CLi_ode / V1i_ode) * IL33TOZO;
dxdt_IL33SST2 = bind_sst2_nM_ode - KEL_SST2 * IL33SST2;

$TABLE
double scale_cl_tab = ALLOM > 0.5 ? pow(WT / REFWT, EXP_CL) : 1.0;
double scale_v_tab = ALLOM > 0.5 ? pow(WT / REFWT, EXP_V) : 1.0;
double CLi_tab = CL * scale_cl_tab;
double V1i_tab = V1 * scale_v_tab;
double V2i_tab = V2 * scale_v_tab;
double CP = CENT / V1i_tab;
double BL_PCT = BL_COMPLEX > 0.0 ? 100.0 * (1.0 - IL33SST2 / BL_COMPLEX) : 0.0;
if (BL_PCT < 0.0) BL_PCT = 0.0;
if (BL_PCT > 100.0) BL_PCT = 100.0;
double TOZO_COMPLEX_MGL = IL33TOZO * (MW_TOZO / 1.0e6);
double TOTAL_CP = CP + TOZO_COMPLEX_MGL;
double K10 = CLi_tab / V1i_tab;
double K12 = Q / V1i_tab;
double K21 = Q / V2i_tab;
double disc = pow(K10 + K12 + K21, 2.0) - 4.0 * K10 * K21;
if (disc < 0.0) disc = 0.0;
double beta = 0.5 * ((K10 + K12 + K21) - sqrt(disc));
double THALF = beta > 0.0 ? log(2.0) / beta : 0.0;
double TE_PCT = TOTAL_CP > 0.0 ? 100.0 * pow(TOTAL_CP, HILL_TE) / (pow(EC50_TE, HILL_TE) + pow(TOTAL_CP, HILL_TE)) : 0.0;
if (TE_PCT < 0.0) TE_PCT = 0.0;
if (TE_PCT > 100.0) TE_PCT = 100.0;
double IL33SST2_OUT = IL33SST2;
double IL33TOZO_OUT = IL33TOZO;

$CAPTURE @annotated
CP          : Free tozorakimab concentration (mg/L)
TOTAL_CP    : Total tozorakimab concentration (mg/L)
IL33SST2_OUT: IL-33/sST2 complex concentration (nM)
IL33TOZO_OUT: IL-33/tozorakimab complex concentration (nM)
BL_PCT      : Mechanistic IL-33/sST2 inhibition from baseline (%)
TE_PCT      : Figure 5-calibrated systemic TE (%)
THALF       : Terminal half-life estimate (days)
'

mod <- mcode("tozorakimab_pkte", 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;
  }
  .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;
  }
  .ref-box a { color: #8b5cf6; }
")

ui <- page_sidebar(
  title = "Tozorakimab PK/TE Simulator",
  theme = app_theme,
  sidebar = sidebar(
    title = "Simulation Settings",
    width = 340,
    h6("Dosing"),
    selectInput("route", "Route", choices = c("Subcutaneous" = "sc", "Intravenous" = "iv"), selected = "sc"),
    sliderInput("dose", "Dose (mg)", min = 30, max = 600, value = 90, step = 30),
    selectInput("interval_days", "Regimen", choices = c("Q2W (14 days)" = 14, "Q4W (28 days)" = 28, "Q6W (42 days)" = 42), selected = 14),
    numericInput("n_doses", "Number of doses", value = 6, min = 1, max = 12),
    hr(),
    h6("Patient / Scenario"),
    sliderInput("wt", "Body weight (kg)", min = 50, max = 110, value = 77.4, step = 0.5),
    checkboxInput("apply_allom", "Apply exploratory weight scaling", value = FALSE),
    hr(),
    h6("Display"),
    checkboxInput("log_scale", "Log Scale (PK Y-axis)", value = FALSE),
    checkboxInput("show_te_target", "Show >95% TE target band", value = TRUE)
  ),
  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, last interval (μg/mL)")
    ),
    div(class = "metric-card metric-warning",
      div(class = "metric-value", textOutput("ctrough")),
      div(class = "metric-label", "Ctrough, end interval (μg/mL)")
    ),
    div(class = "metric-card metric-primary",
      div(class = "metric-value", textOutput("auc")),
      div(class = "metric-label", "AUC0-τ, last interval (μg·day/mL)")
    ),
    div(class = "metric-card metric-info",
      div(class = "metric-value", textOutput("thalf")),
      div(class = "metric-label", "Terminal t½ (days)")
    )
  ),
  card(
    card_header("Serum Tozorakimab Concentration-Time Profile"),
    full_screen = TRUE,
    plotOutput("pkPlot", height = "500px")
  ),
  card(
    card_header("Systemic Target Engagement"),
    full_screen = TRUE,
    plotOutput("tePlot", height = "420px")
  ),
  navset_card_underline(
    title = "Drug Information",
    nav_panel(
      "Model Information",
      div(
        style = "padding: 10px 4px;",
        tags$h4("Tozorakimab mechanistic popPK/TE model"),
        tags$p(tags$strong("Structure:"), " Two-compartment SC/IV monoclonal antibody model with mechanistic IL-33 / soluble ST2 target-engagement in the central compartment."),
        tags$ul(
          tags$li(tags$strong("Clearance:"), " 0.87 L/day"),
          tags$li(tags$strong("Central volume:"), " 12.64 L"),
          tags$li(tags$strong("Peripheral volume:"), " 2.61 L (fixed)"),
          tags$li(tags$strong("Intercompartmental clearance:"), " 0.21 L/day (fixed)"),
          tags$li(tags$strong("SC absorption rate (Ka):"), " 0.48 day⁻¹"),
          tags$li(tags$strong("SC bioavailability:"), " 45%"),
          tags$li(tags$strong("Observed half-life:"), " 11.7–17.3 days in phase 1 cohorts")
        ),
        tags$h5("Clinical context"),
        tags$p("Tozorakimab is a human IgG1 anti-IL-33 monoclonal antibody studied in healthy volunteers and patients with mild COPD. The published simulations showed >95% systemic IL-33/sST2 inhibition at doses above 90 mg across Q2W, Q4W, and Q6W SC regimens."),
        tags$p("The PK panel uses the published two-compartment popPK model. The displayed systemic TE curve is calibrated to reproduce the published Figure 5 dose-response while retaining the manuscript-derived biomarker states in the background model."),
        tags$h5("Covariates"),
        tags$p("No statistically significant covariate effects on PK were retained in the final published model. The optional weight control applies exploratory standard mAb allometry for scenario analysis only; leave it off for paper-faithful simulations.")
      )
    ),
    nav_panel(
      "References",
      div(class = "ref-box",
        tags$h5("Key references"),
        tags$ol(
          tags$li("Sadiq MW, Yu H, et al. Population pharmacokinetic/target engagement modelling of tozorakimab in healthy volunteers and patients with chronic obstructive pulmonary disease. Br J Clin Pharmacol. 2024."),
          tags$li("Reid J, et al. First-in-human phase 1 study of tozorakimab in healthy volunteers and mild COPD participants. Clin Pharmacol Ther. 2024.")
        ),
        tags$h5("Therapeutic context"),
        tags$ul(
          tags$li(tags$strong("Class:"), " Anti-IL-33 monoclonal antibody"),
          tags$li(tags$strong("Therapeutic area:"), " Respiratory and inflammatory disease (COPD-focused early development)"),
          tags$li(tags$strong("Routes evaluated:"), " Subcutaneous and intravenous"),
          tags$li(tags$strong("Primary PD readout:"), " Inhibition of circulating IL-33/sST2 complex")
        )
      )
    )
  ),
  div(
    style = "text-align: center; padding: 20px; margin-top: 30px; border-top: 1px solid #e9ecef; color: #6c757d; font-size: 12px;",
    "Powered by ",
    tags$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_data <- reactive({
    interval_days <- as.numeric(input$interval_days)
    n_doses <- as.integer(input$n_doses)
    shiny::req(!is.na(interval_days), !is.na(n_doses), n_doses >= 1)

    dosing_cmt <- if (identical(input$route, "iv")) 2 else 1
    addl_doses <- max(n_doses - 1, 0)
    sim_end <- max(interval_days * n_doses, interval_days)

    ev1 <- ev(
      amt = input$dose,
      cmt = dosing_cmt,
      ii = interval_days,
      addl = addl_doses
    )

    out <- mod %>%
      param(
        WT = input$wt,
        ALLOM = ifelse(isTRUE(input$apply_allom), 1, 0)
      ) %>%
      ev(ev1) %>%
      mrgsim(end = sim_end, delta = 0.25) %>%
      as.data.frame() |>
      mutate(
        time_days = time,
        interval_days = interval_days,
        route_label = ifelse(input$route == "iv", "IV", "SC")
      )

    out
  })

  steady_window <- reactive({
    d <- sim_data()
    interval_days <- as.numeric(input$interval_days)
    end_time <- max(d$time_days, na.rm = TRUE)
    start_time <- max(end_time - interval_days, 0)
    d |>
      dplyr::filter(time_days >= start_time, time_days <= end_time)
  })

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

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

  output$auc <- renderText({
    d <- steady_window()
    shiny::req(nrow(d) > 1)
    auc_val <- sum(diff(d$time_days) * (head(d$TOTAL_CP, -1) + tail(d$TOTAL_CP, -1)) / 2)
    sprintf("%.1f", auc_val)
  })

  output$thalf <- renderText({
    d <- sim_data()
    shiny::req(nrow(d) > 0)
    sprintf("%.1f", d$THALF[1])
  })

  output$pkPlot <- renderPlot({
    d <- sim_data()
    shiny::req(nrow(d) > 0)

    d_plot <- if (isTRUE(input$log_scale)) {
      d |>
        dplyr::filter(TOTAL_CP > 0.001)
    } else {
      d
    }

    shiny::req(nrow(d_plot) > 0)

    p <- ggplot(d_plot, aes(x = time_days, y = TOTAL_CP)) +
      geom_line(color = "#8b5cf6", linewidth = 0.9) +
      labs(
        x = "Time (days)",
        y = "Total tozorakimab concentration (μg/mL)",
        title = paste0("Tozorakimab ", input$dose, " mg ", toupper(input$route), " every ", as.numeric(input$interval_days), " days")
      ) +
      theme_minimal(base_size = 14)

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

    p
  })

  output$tePlot <- renderPlot({
    d <- sim_data()
    shiny::req(nrow(d) > 0)

    p <- ggplot(d, aes(x = time_days, y = TE_PCT))

    if (isTRUE(input$show_te_target)) {
      p <- p +
        annotate("rect", xmin = -Inf, xmax = Inf, ymin = 95, ymax = 100, fill = "#10b981", alpha = 0.15) +
        geom_hline(yintercept = 95, linetype = "dashed", color = "#10b981", linewidth = 0.8)
    }

    p +
      geom_line(color = "#0dcaf0", linewidth = 0.9) +
      labs(
        x = "Time (days)",
        y = "IL-33/sST2 inhibition from baseline (%)",
        title = "Predicted systemic target engagement"
      ) +
      coord_cartesian(ylim = c(0, 100)) +
      theme_minimal(base_size = 14)
  })
}

shinyApp(ui = ui, server = server)