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

# MgSO4·7H2O conversion constant (MW = 246.47 g/mol)
MMOL_PER_G <- 1000 / 246.47  # 4.057 mmol per gram of MgSO4·7H2O

# ── mrgsolve model ──────────────────────────────────────────────────────────
model_code <- '
$PARAM @annotated
CL      : 4.81   : Typical clearance (L/h)
V       : 15.6   : Typical volume of distribution (L)
KA      : 0.317  : IM absorption rate constant (1/h)
F1      : 0.862  : IM bioavailability (fraction)
BL      : 0.85   : Endogenous baseline magnesium (mmol/L)
WT      : 55     : Body weight (kg)
CRCONC  : 0.8    : Serum creatinine (mg/dl)
H1      : 0.692  : Weight exponent on V
H2      : 1.48   : Creatinine exponent on CL

$CMT @annotated
DEPOT : IM absorption depot (mmol)
CENT  : Central compartment (mmol)

$MAIN
double Vi  = V * pow(WT / 55.0, H1);
double CLi = CL * pow(0.8 / CRCONC, H2);
F_DEPOT = F1;

$ODE
dxdt_DEPOT = -KA * DEPOT;
dxdt_CENT  = KA * DEPOT - (CLi / Vi) * CENT;

$TABLE
double CP_exog  = CENT / Vi;
double CP_total = CP_exog + BL;

$CAPTURE @annotated
CP_total : Total serum magnesium (mmol/L)
CP_exog  : Exogenous drug-derived magnesium (mmol/L)
'

mod <- mcode("magnesium_sulfate", model_code)

# ── 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 = "Magnesium Sulphate PK Simulator — Pre-eclampsia / Eclampsia",
  theme = app_theme,

  sidebar = sidebar(
    title = "Simulation Settings",
    width = 350,

    h6("Regimen"),
    radioButtons("route", NULL,
      choices = c("IV only" = "iv", "IM only" = "im", "Compare IV vs IM" = "both"),
      selected = "both"
    ),

    hr(), h6("IV Settings"),
    conditionalPanel("input.route !== 'im'",
      sliderInput("iv_load_g", "IV Loading Dose (g MgSO\u2084)", min = 4, max = 8, value = 4, step = 1),
      sliderInput("iv_maint_g_h", "IV Maintenance Rate (g/h)", min = 0.5, max = 2.0, value = 1.0, step = 0.25)
    ),

    conditionalPanel("input.route === 'im'",
      tags$p(style = "color:#6c757d; font-size:12px;", "IV-only settings hidden for IM regimen.")
    ),

    hr(), h6("IM Settings"),
    conditionalPanel("input.route !== 'iv'",
      sliderInput("im_load_iv_g",  "IM Protocol IV Load (g)",       min = 2, max = 6,  value = 4, step = 1),
      sliderInput("im_load_im_g",  "IM Loading Dose (g MgSO\u2084)", min = 5, max = 15, value = 10, step = 1),
      sliderInput("im_maint_g",    "IM Maintenance Dose (g Q4H)",   min = 3, max = 7,  value = 5, step = 0.5)
    ),

    conditionalPanel("input.route === 'iv'",
      tags$p(style = "color:#6c757d; font-size:12px;", "IM settings hidden for IV regimen.")
    ),

    sliderInput("sim_hours", "Simulation Duration (h)", min = 12, max = 24, value = 20, step = 2),

    hr(), h6("Patient Characteristics"),
    sliderInput("wt",     "Body Weight (kg)",          min = 40, max = 100, value = 55, step = 5),
    sliderInput("crconc", "Serum Creatinine (mg/dl)",  min = 0.4, max = 1.5, value = 0.8, step = 0.1),

    hr(),
    checkboxInput("show_therapeutic", "Show Therapeutic Window", value = TRUE),
    checkboxInput("log_scale",        "Log Scale (Y-axis)",       value = FALSE)
  ),

  # ── Metric cards ────────────────────────────────────────────────────────
  tags$p(id = "metrics_note",
    style = "font-size: 11px; color: #6c757d; margin: 4px 0 0 6px;",
    textOutput("metrics_label", inline = 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", "Peak Mg (mmol/L)")),
    div(class = "metric-card metric-warning",
        div(class = "metric-value", textOutput("ctrough")),
        div(class = "metric-label", "Mg at 12h (mmol/L)")),
    div(class = "metric-card metric-primary",
        div(class = "metric-value", textOutput("auc")),
        div(class = "metric-label", "AUC\u2080\u208b\u00b9\u00b2h (mmol\u00b7h/L)")),
    div(class = "metric-card metric-info",
        div(class = "metric-value", textOutput("thalf")),
        div(class = "metric-label", "t\u00bd (h)"))
  ),

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

  # ── Info tabs ────────────────────────────────────────────────────────────
  navset_card_underline(
    title = "Drug Information",
    nav_panel("Model Information", markdown("
## Magnesium Sulphate (MgSO\u2084) \u2014 Population PK Model

**Study:** Salinger et al. (2013), *BJOG* 120:894\u2013900  
**Subjects:** 258 pregnant women with pre-eclampsia (India)  
**Structure:** 1-compartment + IM first-order absorption  
**Software:** NONMEM 7 (mixed-effects, proportional residual error)

### Population PK Parameters (Final Model)

| Parameter | Value | Units | %SE |
|-----------|-------|-------|-----|
| Clearance (CL) | 4.81 | L/h | 10% |
| Volume of distribution (V) | 15.6 | L | 8% |
| IM absorption rate (K\u2090) | 0.317 | h\u207b\u00b9 | 16% |
| IM bioavailability (F) | 86.2% | \u2014 | 3.2% |
| Endogenous baseline (BL) | 0.85 | mmol/L | \u2014 |
| Residual CV | 22.9% | \u2014 | \u2014 |

### Covariate Effects
- **Weight \u2192 Volume:** V\u1d62 = V \u00d7 (WT\u1d62/55)\u2070\u02b7\u2076\u2079\u00b2
- **Creatinine \u2192 Clearance:** CL\u1d62 = CL \u00d7 (0.8/SCr\u1d62)\u00b9\u02b7\u2074\u2078 (SCr in mg/dl; reference = 0.8 mg/dl = 61 \u00b5mol/L)

Reference weight = **55 kg** (median study population)

### Therapeutic Serum Magnesium Levels

| Level (mmol/L) | mg/dl | mEq/L | Clinical significance |
|----------------|-------|-------|----------------------|
| < 2.0 | < 4.8 | < 4 | Potentially sub-therapeutic |
| **2.0 \u2013 3.5** | **4.8 \u2013 8.5** | **4 \u2013 7** | **Therapeutic (seizure prophylaxis)** |
| 3.5 \u2013 5.0 | 8.5 \u2013 12 | 7 \u2013 10 | Loss of patellar reflexes |
| 5.0 \u2013 6.5 | 12 \u2013 15.8 | 10 \u2013 13 | Respiratory paralysis risk |
| > 7.5 | > 18 | > 15 | Cardiac conduction changes |

*Note: 1 mmol/L \u2248 2.43 mg/dl \u2248 2 mEq/L for Mg\u00b2\u207a*

### Standard MAGPIE Trial Dosing
- **IV:** 4 g loading over 20 min \u2192 1 g/h maintenance infusion
- **IM:** 4 g IV loading + 10 g IM loading \u2192 5 g IM Q4H
    ")),
    nav_panel("References", div(class = "ref-box",
      tags$h5("\U0001F4DA Primary Reference"),
      tags$ol(
        tags$li(
          tags$strong("Salinger DH, Mundle S, Regi A, Bracken H, Winikoff B, Vicini P, Easterling T. (2013)"),
          " Magnesium sulphate for prevention of eclampsia: are intramuscular and intravenous regimens equivalent? A population pharmacokinetic study. ",
          tags$em("BJOG"), " 120:894\u2013900. ",
          tags$a(href = "https://doi.org/10.1111/1471-0528.12222", target = "_blank",
                 "doi:10.1111/1471-0528.12222")
        ),
        tags$li(
          "The Magpie Trial Collaboration Group. (2002) Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial. ",
          tags$em("Lancet"), " 359:1877\u201390."
        ),
        tags$li(
          "Lu J, Pfister M, Ferrari P, Chen G, Sheiner L. (2002) Pharmacokinetic-pharmacodynamic modelling of magnesium plasma concentration and blood pressure in preeclampsia. ",
          tags$em("Clin Pharmacokinet"), " 41:1105\u201313."
        ),
        tags$li(
          "Chuan FS, Charles BG, Boyle RK, Rasiah RL. (2001) Population pharmacokinetics of magnesium in preeclampsia. ",
          tags$em("Am J Obstet Gynecol"), " 185:593\u20139."
        )
      ),
      tags$h5("\U0001F48A Therapeutic Context"),
      tags$ul(
        tags$li(tags$strong("Class:"), " Anticonvulsant / electrolyte replenisher"),
        tags$li(tags$strong("Indication:"), " Prevention and treatment of seizures in pre-eclampsia/eclampsia"),
        tags$li(tags$strong("Routes:"), " IV infusion, deep IM injection (gluteal)"),
        tags$li(tags$strong("Elimination:"), " Renal filtration (no hepatic metabolism); CL \u2248 GFR"),
        tags$li(tags$strong("Monitoring:"), " Serum Mg, deep tendon reflexes, respiratory rate (\u226512/min), urine output (\u226525 mL/h)"),
        tags$li(tags$strong("Antidote:"), " Calcium gluconate 1 g IV (for overdose)")
      )
    ))
  ),

  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_one_route <- function(route_type) {
    shiny::req(input$wt, input$crconc, input$sim_hours)
    end_h <- input$sim_hours
    load_dur_h <- 20 / 60  # 20-min IV bolus

    if (route_type == "iv") {
      shiny::req(input$iv_load_g, input$iv_maint_g_h)
      load_mmol <- input$iv_load_g * MMOL_PER_G
      maint_rate <- input$iv_maint_g_h * MMOL_PER_G   # mmol/h
      maint_dur  <- max(0, end_h - load_dur_h)

      ev_load  <- ev(time = 0,          amt = load_mmol,             cmt = 2,
                     rate = load_mmol / load_dur_h)
      ev_maint <- ev(time = load_dur_h, amt = maint_rate * maint_dur, cmt = 2,
                     rate = maint_rate)
      evs <- c(ev_load, ev_maint)

    } else {
      shiny::req(input$im_load_iv_g, input$im_load_im_g, input$im_maint_g)
      iv_load_mmol <- input$im_load_iv_g  * MMOL_PER_G
      im_load_mmol <- input$im_load_im_g  * MMOL_PER_G
      im_maint_mmol <- input$im_maint_g   * MMOL_PER_G
      n_addl <- max(0L, as.integer(floor((end_h - 4) / 4)) - 1L)

      ev_iv_load  <- ev(time = 0, amt = iv_load_mmol,  cmt = 2,
                        rate = iv_load_mmol / load_dur_h)
      ev_im_load  <- ev(time = 0, amt = im_load_mmol,  cmt = 1)
      ev_im_maint <- ev(time = 4, amt = im_maint_mmol, cmt = 1, ii = 4, addl = n_addl)
      evs <- c(ev_iv_load, ev_im_load, ev_im_maint)
    }

    mod %>%
      param(WT = input$wt, CRCONC = input$crconc) %>%
      ev(evs) %>%
      mrgsim(end = end_h, delta = 0.1) %>%
      as.data.frame() |>
      dplyr::mutate(route = route_type)
  }

  sim_data <- reactive({
    shiny::req(input$route)
    if (input$route == "iv") {
      sim_one_route("iv")
    } else if (input$route == "im") {
      sim_one_route("im")
    } else {
      bind_rows(sim_one_route("iv"), sim_one_route("im"))
    }
  })

  primary_data <- reactive({
    d <- sim_data()
    if (input$route == "both") d |> dplyr::filter(route == "iv") else d
  })

  output$metrics_label <- renderText({
    if (input$route == "both") "Metrics shown for IV regimen" else ""
  })

  output$cmax <- renderText({
    d <- primary_data()
    shiny::req(nrow(d) > 0)
    sprintf("%.2f", max(d$CP_total, na.rm = TRUE))
  })

  output$ctrough <- renderText({
    d <- primary_data()
    shiny::req(nrow(d) > 0)
    d12 <- d |> dplyr::filter(abs(time - 12) < 0.15)
    if (nrow(d12) == 0) return("\u2014")
    sprintf("%.2f", d12$CP_total[1])
  })

  output$auc <- renderText({
    d <- primary_data()
    shiny::req(nrow(d) > 0)
    d_auc <- d |> dplyr::filter(time <= 12)
    auc <- sum(diff(d_auc$time) * (head(d_auc$CP_total, -1) + tail(d_auc$CP_total, -1)) / 2)
    sprintf("%.1f", auc)
  })

  output$thalf <- renderText({
    shiny::req(input$wt, input$crconc)
    Vi  <- 15.6 * (input$wt / 55)^0.692
    CLi <- 4.81 * (0.8 / max(input$crconc, 0.1))^1.48
    sprintf("%.1f", log(2) / (CLi / Vi))
  })

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

    d_plot <- if (input$log_scale) d |> dplyr::filter(CP_total > 0.01) else d

    route_colors <- c("iv" = "#8b5cf6", "im" = "#f59e0b")
    route_labels <- c("iv" = "IV Regimen", "im" = "IM Regimen")

    p <- ggplot(d_plot, aes(x = time, y = CP_total, color = route, group = route))

    if (input$show_therapeutic) {
      p <- p +
        annotate("rect", xmin = -Inf, xmax = Inf, ymin = 2.0, ymax = 3.5,
                 fill = "#10b981", alpha = 0.12) +
        annotate("rect", xmin = -Inf, xmax = Inf, ymin = 3.5, ymax = 5.0,
                 fill = "#f59e0b", alpha = 0.10) +
        geom_hline(yintercept = 2.0, linetype = "dashed", color = "#10b981",
                   alpha = 0.8, linewidth = 0.5) +
        geom_hline(yintercept = 3.5, linetype = "dashed", color = "#f59e0b",
                   alpha = 0.8, linewidth = 0.5) +
        annotate("text", x = max(d$time, na.rm = TRUE) * 0.98, y = 2.1,
                 label = "Therapeutic \u2265 2.0 mmol/L", hjust = 1, size = 3.2, color = "#10b981") +
        annotate("text", x = max(d$time, na.rm = TRUE) * 0.98, y = 3.6,
                 label = "Reflex loss \u2265 3.5 mmol/L", hjust = 1, size = 3.2, color = "#f59e0b")
    }

    p <- p +
      geom_line(linewidth = 1.0) +
      scale_color_manual(values = route_colors, labels = route_labels,
                         breaks = names(route_colors)) +
      labs(
        x     = "Time (hours)",
        y     = "Serum Magnesium (mmol/L)",
        title = paste0("MgSO\u2084 PK \u2014 WT: ", input$wt,
                       " kg | SCr: ", input$crconc, " mg/dl"),
        color = NULL
      ) +
      theme_minimal(base_size = 14) +
      theme(legend.position = "top", legend.text = element_text(size = 12))

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

shinyApp(ui = ui, server = server)