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

# ── Levamisole Two-Compartment Oral PK Model ──
# Based on allometric 2CM joint fitting across 8 species (2 bird, 6 mammalian)
# Source: Cheng CF, Jeong YS, Jusko WJ (2026) J Pharm Invest 56:171-183
# Human parameters from Table 1 (CL) and Table 2 (V1, V2, Q allometric)
# Ka and F estimated/fixed in joint model fitting

model_code <- '
$PARAM @annotated
CL   : 17.5   : Clearance (L/h) at 70 kg
V1   : 88.1   : Central volume (L) at 70 kg
V2   : 40.3   : Peripheral volume (L) at 70 kg
Q    : 17.5   : Intercompartmental clearance (L/h) at 70 kg
KA   : 1.702  : Absorption rate constant (1/h)
F1   : 0.66   : Oral bioavailability
WT   : 70     : Body weight (kg)

$CMT @annotated
DEPOT  : Oral absorption depot (mg)
CENT   : Central compartment (mg)
PERIPH : Peripheral compartment (mg)

$MAIN
double CLi  = CL * pow(WT / 70.0, 0.75);
double V1i  = V1 * (WT / 70.0);
double V2i  = V2 * (WT / 70.0);
double Qi   = Q * pow(WT / 70.0, 0.75);
F_DEPOT = F1;

$ODE
dxdt_DEPOT  = -KA * DEPOT;
dxdt_CENT   = KA * DEPOT - (CLi / V1i + Qi / V1i) * CENT + (Qi / V2i) * PERIPH;
dxdt_PERIPH = (Qi / V1i) * CENT - (Qi / V2i) * PERIPH;

$TABLE
double CP = CENT / V1i;

$CAPTURE @annotated
CP : Plasma concentration (mg/L)
'

mod <- mcode("levamisole", model_code)

# ── PKPDBuilder Brand Theme ──
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 ──
ui <- page_sidebar(
  title = "Levamisole PK Simulator",
  theme = app_theme,

  sidebar = sidebar(
    title = "Simulation Settings",
    width = 340,

    h6("Dosing"),
    numericInput("dose", "Dose (mg)", value = 150, min = 10, max = 500, step = 25),
    sliderInput("interval", "Dosing Interval (h)", min = 6, max = 24, value = 8, step = 2),
    numericInput("n_days", "Duration (days)", value = 3, min = 1, max = 14),

    hr(),
    h6("Patient"),
    sliderInput("wt", "Weight (kg)", min = 40, max = 150, value = 70, step = 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")),
      div(class = "metric-label", "Cmax (mg/L)")
    ),
    div(class = "metric-card metric-warning",
      div(class = "metric-value", textOutput("ctrough")),
      div(class = "metric-label", "Ctrough (mg/L)")
    ),
    div(class = "metric-card metric-primary",
      div(class = "metric-value", textOutput("auc")),
      div(class = "metric-label", paste0("AUC", "\u2080", "-", "\u03C4", " (mg\u00B7h/L)"))
    ),
    div(class = "metric-card metric-info",
      div(class = "metric-value", textOutput("thalf")),
      div(class = "metric-label", paste0("t\u00BD", " (h)"))
    )
  ),

  # ── PK Plot ──
  card(
    card_header("Concentration-Time Profile"),
    full_screen = TRUE,
    plotOutput("pkPlot", height = "500px")
  ),

  # ── Tabbed Info ──
  navset_card_underline(
    title = "Drug Information",
    nav_panel("Model Information", markdown("
## Levamisole — Two-Compartment Oral PK Model

**Structure:** Two-compartment with first-order absorption and allometric weight scaling  
**Source:** Meta-analysis across 8 species (duck, rabbit, chicken, goat, dog, sheep, pig, human)

### Human PK Parameters (at 70 kg)
| Parameter | Value | Description |
|-----------|-------|-------------|
| CL | 17.5 L/h | Systemic clearance |
| V1 (Vp) | 88.1 L | Central volume of distribution |
| V2 (Vt) | 40.3 L | Peripheral volume of distribution |
| Q (CLd) | 17.5 L/h | Distributional clearance |
| Ka | 1.702 h\u207B\u00B9 | Absorption rate constant |
| F | 0.66 | Oral bioavailability |
| t\u00BD | ~5.7 h | Terminal elimination half-life |

### Allometric Scaling (Cross-Species)
- **V1** = 0.339 \u00D7 BW^1.31 (exponent from joint fitting)
- **V2** = 0.937 \u00D7 BW^0.885
- **Q** = 0.352 \u00D7 BW^0.920
- **CL** scaled with standard 0.75 exponent (within-human range)

### Pharmacological Context
- **Immunomodulant** — enhances T-cell function, used adjunctively in colon cancer (with 5-FU)
- **Antiparasitic** — broad-spectrum anthelmintic across veterinary and human medicine
- **Absorption:** Rapid (Tmax ~1.5 h), high solubility (210 mg/mL), BCS debated (Class I vs III)
- **Metabolism:** Extensive hepatic; p-hydroxylation is key pathway in humans; renal CL only ~5% of total
- **Bioavailability:** Remarkably consistent across species (50-80%), except goats

### Clinical Dosing
- **Antiparasitic:** 150 mg single oral dose (2.5 mg/kg)
- **Cancer adjuvant:** 50 mg TID \u00D7 3 days, every 2 weeks (with 5-FU)
- **Immunomodulation:** 50 mg/day or 2.5 mg/kg intermittently
    ")),
    nav_panel("References", div(class = "ref-box",
      tags$h5("\U0001F4DA Key References"),
      tags$ol(
        tags$li("Cheng CF, Jeong YS, Jusko WJ (2026) Meta-analysis of levamisole absorption and disposition across diverse species using a minimal physiologically-based pharmacokinetic model. J Pharm Invest 56:171-183. ",
                tags$a(href = "https://doi.org/10.1007/s40005-025-00770-6", target = "_blank", "DOI")),
        tags$li("Kouassi E et al. (1986) Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine. Biopharm Drug Dispos 7(1):71-89"),
        tags$li("Luyckx M et al. (1982) Pharmacokinetics of levamisole in healthy subjects and cancer patients. Eur J Drug Metab Pharmacokinet 7:247-254"),
        tags$li("Kambayashi A et al. (2023) Biowaiver monograph for immediate-release dosage forms: levamisole hydrochloride. J Pharm Sci 112(3):634-639")
      ),
      tags$h5("\U0001F48A Therapeutic Context"),
      tags$ul(
        tags$li(tags$strong("Class:"), " Imidazothiazole; immunomodulant / anthelmintic"),
        tags$li(tags$strong("MW:"), " 204.29 g/mol; pKa = 6.98"),
        tags$li(tags$strong("Route:"), " Oral (high solubility, rapid absorption)"),
        tags$li(tags$strong("Metabolism:"), " Hepatic oxidation & hydrolysis; p-hydroxylation (major in humans)"),
        tags$li(tags$strong("Note:"), " FDA-approved in 1990 for colon cancer adjuvant (withdrawn 2000); widely used in veterinary medicine worldwide")
      )
    ))
  ),

  # ── Footer ──
  div(style = "text-align: center; padding: 20px; margin-top: 30px;
      border-top: 1px solid #e9ecef; color: #6c757d; font-size: 12px;",
    "Powered by ",
    tags$a(href = "https://www.pkpdbuilder.com", target = "_blank",
           style = "color: #8b5cf6; font-weight: 500;", "PKPDBuilder.com"),
    " \u2022 Built by Sunny \u2600\uFE0F (Husain Attarwala's AI Assistant)",
    br(),
    tags$span(style = "font-size: 10px;",
      "For research and educational purposes only. Not for clinical decision-making.")
  )
)

# ── Server ──
server <- function(input, output, session) {

  sim_data <- reactive({
    shiny::req(input$dose > 0, input$interval > 0, input$n_days >= 1)
    n_doses <- max(1, floor(input$n_days * 24 / input$interval))
    ev1 <- ev(amt = input$dose, cmt = 1, ii = input$interval, addl = n_doses - 1)
    mod %>%
      param(WT = input$wt) %>%
      ev(ev1) %>%
      mrgsim(end = input$n_days * 24, delta = 0.1) %>%
      as.data.frame() |>
      mutate(time_h = time)
  })

  # Steady-state interval data (last dosing interval)
  last_interval <- reactive({
    d <- sim_data()
    last_start <- max(0, (input$n_days - 1) * 24)
    d |> dplyr::filter(time >= last_start)
  })

  output$cmax <- renderText({
    d <- last_interval()
    shiny::req(nrow(d) > 0)
    sprintf("%.3f", max(d$CP, na.rm = TRUE))
  })

  output$ctrough <- renderText({
    d <- last_interval()
    shiny::req(nrow(d) > 0)
    sprintf("%.4f", min(d$CP[d$CP > 0], na.rm = TRUE))
  })

  output$auc <- renderText({
    d <- sim_data()
    shiny::req(nrow(d) > 1)
    last_start <- max(0, (input$n_days - 1) * 24)
    last <- d |> dplyr::filter(time >= last_start, time <= last_start + input$interval)
    shiny::req(nrow(last) > 1)
    auc_val <- sum(diff(last$time) * (head(last$CP, -1) + tail(last$CP, -1)) / 2)
    sprintf("%.2f", auc_val)
  })

  output$thalf <- renderText({
    wt <- input$wt
    CLi  <- 17.5 * (wt / 70)^0.75
    V1i  <- 88.1 * (wt / 70)
    V2i  <- 40.3 * (wt / 70)
    Qi   <- 17.5 * (wt / 70)^0.75
    k10  <- CLi / V1i
    k12  <- Qi / V1i
    k21  <- Qi / V2i
    s    <- k10 + k12 + k21
    p    <- k10 * k21
    disc <- s^2 - 4 * p
    disc <- max(disc, 0)
    beta_val <- (s - sqrt(disc)) / 2
    if (beta_val > 0) {
      sprintf("%.1f", log(2) / beta_val)
    } else {
      "N/A"
    }
  })

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

    d_plot <- if (input$log_scale) d |> dplyr::filter(CP > 0.0001) else d
    shiny::req(nrow(d_plot) > 0)

    p <- ggplot(d_plot, aes(x = time_h, y = CP)) +
      geom_line(color = "#8b5cf6", linewidth = 0.9) +
      labs(
        x = "Time (hours)",
        y = "Concentration (mg/L)",
        title = paste0("Levamisole ", input$dose, " mg Q", input$interval,
                       "H \u00D7 ", input$n_days, " days (",  input$wt, " kg)")
      ) +
      theme_minimal(base_size = 14) +
      theme(
        plot.title = element_text(face = "bold", size = 15),
        panel.grid.minor = element_line(color = "#f0f0f0")
      )

    if (input$log_scale) {
      p <- p + scale_y_log10(
        labels = scales::label_number(drop0trailing = TRUE)
      )
    }

    p
  })
}

shinyApp(ui = ui, server = server)