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

# ---------------------------------------------------------------------------
# mrgsolve PBPK-derived parent–metabolite model
# Based on: Sharma et al. (2020) Environ Res — PBPK model for flutamide
# Parameters calibrated to reproduce Radwanski et al. (1989) human PK data
# ---------------------------------------------------------------------------
model_code <- '
$PARAM @annotated
CL     : 260    : Apparent clearance - flutamide (L/h)
Vc     : 2200   : Volume of distribution - flutamide (L)
KA     : 0.80   : Absorption rate constant (1/h)
F1     : 0.90   : Oral bioavailability (fraction)
Fm     : 0.85   : Fraction metabolised to 2-OH-flutamide via CYP1A2
CLm    : 12.5   : Apparent clearance - 2-OH-flutamide (L/h)
Vm     : 174    : Volume of distribution - 2-OH-flutamide (L)
WT     : 70     : Body weight (kg)
CYP1A2 : 1.0   : CYP1A2 activity (fraction of normal)

$CMT @annotated
DEPOT : Oral depot (mg)
FLU   : Flutamide central compartment (mg)
OH    : 2-OH-Flutamide central compartment (mg)

$MAIN
F_DEPOT = F1;

$ODE
double ke   = CL  * pow(WT / 70.0, 0.75) * CYP1A2 / (Vc  * (WT / 70.0));
double kem  = CLm * pow(WT / 70.0, 0.75)            / (Vm  * (WT / 70.0));

dxdt_DEPOT = -KA * DEPOT;
dxdt_FLU   =  KA * DEPOT - ke  * FLU;
dxdt_OH    =  Fm * ke    * FLU - kem * OH;

$TABLE
double Vci  = Vc * (WT / 70.0);
double Vmi  = Vm * (WT / 70.0);
double CP_flu = (FLU / Vci) * 1000.0;   // ng/mL
double CP_oh  = (OH  / Vmi) * 1000.0;   // ng/mL

$CAPTURE CP_flu CP_oh
'

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

# ---------------------------------------------------------------------------
# Theme
# ---------------------------------------------------------------------------
app_theme <- bs_theme(
  version    = 5,
  bootswatch = "flatly",
  primary    = "#8b5cf6"
) |> bs_add_rules("
  .metric-card { background: #f8f9fa; border-radius: 8px; padding: 15px;
                 margin: 4px; text-align: center; border: 1px solid #dee2e6; }
  .metric-value { font-size: 22px; font-weight: bold; color: #2c3e50; }
  .metric-label { font-size: 12px; color: #7f8c8d; }
  .metric-unit  { font-size: 10px; color: #adb5bd; }
  .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; }
  .kp-table { font-size: 12px; }
")

# ---------------------------------------------------------------------------
# UI
# ---------------------------------------------------------------------------
ui <- page_sidebar(
  title  = "Flutamide PBPK Simulator",
  theme  = app_theme,

  sidebar = sidebar(
    title = "Simulation Settings", width = 330,

    h6("Dosing"),
    sliderInput("dose", "Dose (mg)",
                min = 125, max = 500, value = 250, step = 125),
    helpText("Standard clinical dose: 250 mg q8h (TID)"),
    sliderInput("interval", "Dosing Interval (h)",
                min = 6, max = 12, value = 8, step = 1),
    numericInput("n_days", "Duration (days)", value = 5, min = 1, max = 14),

    hr(),
    h6("Patient Characteristics"),
    sliderInput("wt", "Weight (kg)", min = 40, max = 130, value = 70, step = 5),

    hr(),
    h6("Pharmacogenomics / Drug Interactions"),
    sliderInput("cyp1a2", "CYP1A2 Activity (fraction)",
                min = 0.1, max = 2.5, value = 1.0, step = 0.1),
    helpText("Normal = 1.0 | Inhibited (fluvoxamine, cipro) = 0.2–0.5 |",
             "Induced (smoking, omeprazole) = 1.5–2.5"),

    hr(),
    checkboxInput("log_scale", "Log Scale (Y-axis)", value = FALSE)
  ),

  # ---- Metric cards -------------------------------------------------------
  layout_column_wrap(
    width = 1/4, fill = FALSE,

    div(class = "metric-card metric-success",
        div(class = "metric-value", textOutput("cmax_flu")),
        div(class = "metric-label", "Flutamide Cmax"),
        div(class = "metric-unit",  "ng/mL — at steady state")),

    div(class = "metric-card metric-warning",
        div(class = "metric-value", textOutput("cmax_oh")),
        div(class = "metric-label", "2-OH-Flutamide Cmax"),
        div(class = "metric-unit",  "ng/mL — active metabolite")),

    div(class = "metric-card metric-primary",
        div(class = "metric-value", textOutput("thalf_flu")),
        div(class = "metric-label", "Flutamide t\u00BD"),
        div(class = "metric-unit",  "hours")),

    div(class = "metric-card metric-info",
        div(class = "metric-value", textOutput("thalf_oh")),
        div(class = "metric-label", "2-OH-Flutamide t\u00BD"),
        div(class = "metric-unit",  "hours"))
  ),

  # ---- Main plot card -----------------------------------------------------
  card(
    full_screen = TRUE,
    min_height  = "500px",
    plotOutput("pkPlot", height = "460px")
  ),

  # ---- Information tabs ---------------------------------------------------
  navset_card_underline(

    nav_panel("Model Information",
      div(style = "padding: 16px;",
        markdown("
## Flutamide PBPK-Derived PK Simulator

**Model Type:** PBPK-derived parent–metabolite (1-compartment per species)  
**Structure:** Oral depot → Flutamide (central) → 2-OH-Flutamide (central)  
**Source:** Sharma RP et al. (2020) *Environmental Research* 183:108948

### PBPK Model Parameters (Human, 70 kg Reference)

| Parameter | Symbol | Value | Units | Source |
|-----------|--------|-------|-------|--------|
| Absorption rate | Ka | 0.80 | h⁻¹ | PBPK (kgut) |
| Oral bioavailability | F | 0.90 | fraction | Estimated |
| Unbound fraction (flutamide) | fu | 0.09 | — | Asakawa et al. (1995) |
| Unbound fraction (Flu-OH) | fu₁ | 0.05 | — | Sjögren et al. (2014) |
| CYP1A2 → Flu-OH Km | Km₁ | 1.113 | mg/L | Sjo et al. (2009) |
| CYP1A2 → Flu-OH Vmax | Vmax₁ | 0.079 | µg/min/mg MSP | Sjo et al. (2009) |
| FLU-6 pathway Km | Km₂ | 23.754 | mg/L | Wen et al. (2008) |
| FLU-1 pathway Km | Km₃ | 82.863 | mg/L | Kobayashi et al. (2012) |
| Flutamide apparent t½ | — | ~5.9 | h | PBPK-derived |
| 2-OH-Flutamide t½ | — | ~9.6 | h | Radwanski (1989) |

### Tissue Partition Coefficients (Kp = tissue/plasma)

| Tissue | Kp | Implication |
|--------|----|-------------|
| Liver | 5.57 | High liver accumulation — hepatotoxicity risk |
| Prostate | 2.17 | 2× plasma — target tissue enrichment |
| Kidney | 2.63 | Renal distribution |
| Fat | 2.78 | Lipophilic storage — prolonged exposure |
| Gonads | 1.70 | Off-target endocrine effects |
| Lung | 1.65 | Modest pulmonary distribution |

### Allometric Scaling
- CL and CLm scaled as BW^0.75
- Vc and Vm scaled linearly with BW
        ")
      )
    ),

    nav_panel("References",
      div(class = "ref-box", style = "margin: 16px;",
        tags$h5("\U0001F4DA Key References"),
        tags$ol(
          tags$li("Sharma RP, Kumar V, Schuhmacher M et al. (2020) Development and evaluation of a harmonized whole body PBPK model for flutamide in rats and its extrapolation to humans. ",
                  tags$em("Environ Res"), " 183:108948."),
          tags$li("Radwanski E, Perentesis G, Symchowicz S, Zampaglione N. (1989) Single and multiple dose pharmacokinetic evaluation of flutamide in normal geriatric volunteers. ",
                  tags$em("J Clin Pharmacol"), " 29:554–558."),
          tags$li("Sjögren E, Tammela TL, Lennernäs B et al. (2014) Pharmacokinetics of injectable modified-release 2-hydroxyflutamide using a semi-physiologically based biopharmaceutical model. ",
                  tags$em("Mol Pharm"), " 11:3097–3111."),
          tags$li("Kobayashi Y et al. (2012) In vitro metabolic data used for IVIVE scaling. ",
                  tags$em("Drug Metab Dispos")),
          tags$li("Asakawa N et al. (1995) Tissue distribution and partition coefficients from in vivo rat studies.")
        ),
        tags$h5("\U0001F48A Therapeutic Context"),
        tags$ul(
          tags$li(tags$strong("Drug class:"), " Non-steroidal antiandrogen (androgen receptor antagonist)"),
          tags$li(tags$strong("Brand:"), " Eulexin® (125 mg capsules, TID = 750 mg/day)"),
          tags$li(tags$strong("Mechanism:"), " Competitive AR blockade — active form is 2-OH-flutamide (Flu-OH)"),
          tags$li(tags$strong("Indication:"), " Stage D2 metastatic prostate cancer (combined with LHRH agonist)"),
          tags$li(tags$strong("Metabolism:"), " CYP1A2 (primary → Flu-OH), nitro-reduction (FLU-6, FLU-1)"),
          tags$li(tags$strong("Black box warning:"), " Hepatotoxicity — monitor LFTs monthly for first 4 months"),
          tags$li(tags$strong("Prostate enrichment:"), " Kp(prostate/plasma) = 2.17 → ~2× higher than plasma")
        )
      )
    )
  ),

  # ---- Footer -------------------------------------------------------------
  div(
    style = "text-align: center; padding: 20px; margin-top: 20px;
             border-top: 1px solid #e9ecef; color: #6c757d; font-size: 12px;",
    "Powered by ",
    tags$a(href = "https://www.pkpdbuilder.com", target = "_blank",
           style = "color: #8b5cf6; font-weight: 500;", "PKPDBuilder.com"),
    " \u2022 Built by Sunny \u2600\uFE0F (Husain Attarwala\u2019s AI Assistant)",
    tags$br(),
    tags$span(
      style = "font-size: 10px;",
      "For research and educational purposes only. Not for clinical decision-making."
    )
  )
)

# ---------------------------------------------------------------------------
# Server
# ---------------------------------------------------------------------------
server <- function(input, output, session) {
  tryCatch(thematic::thematic_shiny(), error = function(e) NULL)

  # Reactive simulation
  sim_data <- reactive({
    shiny::req(input$dose, input$interval, input$n_days, input$wt, input$cyp1a2)

    n_doses <- max(1L, floor(input$n_days * 24 / input$interval))
    ev1 <- ev(amt = input$dose, cmt = 1, ii = input$interval, addl = n_doses - 1L)

    mod |>
      param(WT = input$wt, CYP1A2 = input$cyp1a2) |>
      ev(ev1) |>
      mrgsim(end = input$n_days * 24, delta = 0.1) |>
      as.data.frame()
  })

  # Helper: last-interval window
  last_interval_data <- reactive({
    d   <- sim_data()
    t0  <- max(0, (input$n_days - 1) * 24)
    dplyr::filter(d, time >= t0)
  })

  # Metric: Flutamide Cmax
  output$cmax_flu <- renderText({
    sprintf("%.1f", max(last_interval_data()$CP_flu, na.rm = TRUE))
  })

  # Metric: 2-OH-Flu Cmax
  output$cmax_oh <- renderText({
    sprintf("%.1f", max(last_interval_data()$CP_oh, na.rm = TRUE))
  })

  # Metric: Flutamide t½
  output$thalf_flu <- renderText({
    shiny::req(input$wt, input$cyp1a2)
    ke <- 260 * (input$wt / 70)^0.75 * input$cyp1a2 / (2200 * (input$wt / 70))
    sprintf("%.1f", log(2) / ke)
  })

  # Metric: 2-OH-Flu t½
  output$thalf_oh <- renderText({
    shiny::req(input$wt)
    kem <- 12.5 * (input$wt / 70)^0.75 / (174 * (input$wt / 70))
    sprintf("%.1f", log(2) / kem)
  })

  # PK plot
  output$pkPlot <- renderPlot({
    d <- sim_data()

    # Long format for both species
    d_long <- tidyr::pivot_longer(
      d,
      cols      = c("CP_flu", "CP_oh"),
      names_to  = "species",
      values_to = "conc"
    ) |>
      dplyr::mutate(species = dplyr::case_when(
        species == "CP_flu" ~ "Flutamide",
        species == "CP_oh"  ~ "2-OH-Flutamide (active)"
      ))

    # Filter near-zero values when log scale requested
    if (input$log_scale) {
      d_long <- dplyr::filter(d_long, conc > 0.01)
    }

    p <- ggplot2::ggplot(d_long, ggplot2::aes(x = time, y = conc, color = species)) +
      ggplot2::geom_line(linewidth = 0.9) +
      ggplot2::scale_color_manual(
        values = c(
          "Flutamide"              = "#8b5cf6",
          "2-OH-Flutamide (active)" = "#f59e0b"
        )
      ) +
      ggplot2::labs(
        x     = "Time (hours)",
        y     = "Plasma Concentration (ng/mL)",
        title = paste0(
          "Flutamide ", input$dose, " mg Q", input$interval, "H — ",
          input$n_days, "-day PK Profile"
        ),
        subtitle = paste0(
          "Weight: ", input$wt, " kg  |  CYP1A2 activity: ",
          input$cyp1a2, "\u00D7  |  Kp(prostate/plasma) = 2.17"
        ),
        color = NULL,
        caption = paste0(
          "PBPK-derived model: Sharma et al. (2020) Environ Res | ",
          "Calibrated to Radwanski et al. (1989) J Clin Pharmacol"
        )
      ) +
      ggplot2::theme_minimal(base_size = 13) +
      ggplot2::theme(
        legend.position  = "top",
        plot.title       = ggplot2::element_text(face = "bold"),
        plot.subtitle    = ggplot2::element_text(color = "#6c757d", size = 10),
        plot.caption     = ggplot2::element_text(color = "#adb5bd", size = 9),
        panel.grid.minor = ggplot2::element_blank()
      )

    if (input$log_scale) {
      p <- p + ggplot2::scale_y_log10(
        labels = scales::label_comma()
      )
    }

    p
  })
}

shinyApp(ui = ui, server = server)