Fix various issues with pharmacokinetics, improved parameters, distinction between adult/child

2026-01-17 20:27:00 +00:00
parent b911fa1e16
commit 6983ce3853
13 changed files with 1505 additions and 115 deletions
--- a/src/App.tsx
+++ b/src/App.tsx
@@ -75,6 +75,7 @@ const MedPlanAssistant = () => {
    addDoseToDay,
    removeDoseFromDay,
    updateDoseInDay,
+    updateDoseFieldInDay,
    sortDosesInDay
  } = useAppState();

@@ -209,6 +210,7 @@ const MedPlanAssistant = () => {
              onAddDose={addDoseToDay}
              onRemoveDose={removeDoseFromDay}
              onUpdateDose={updateDoseInDay}
+              onUpdateDoseField={updateDoseFieldInDay}
              onSortDoses={sortDosesInDay}
              t={t}
            />
--- a/src/components/day-schedule.tsx
+++ b/src/components/day-schedule.tsx
@@ -17,7 +17,7 @@ import { FormNumericInput } from './ui/form-numeric-input';
 import { Tooltip, TooltipContent, TooltipTrigger } from './ui/tooltip';
 import { IconButtonWithTooltip } from './ui/icon-button-with-tooltip';
 import CollapsibleCardHeader from './ui/collapsible-card-header';
-import { Plus, Copy, Trash2, ArrowDownAZ, TrendingUp, TrendingDown } from 'lucide-react';
+import { Plus, Copy, Trash2, ArrowDownAZ, TrendingUp, TrendingDown, Utensils } from 'lucide-react';
 import type { DayGroup } from '../constants/defaults';

 interface DayScheduleProps {
@@ -28,6 +28,7 @@ interface DayScheduleProps {
  onAddDose: (dayId: string) => void;
  onRemoveDose: (dayId: string, doseId: string) => void;
  onUpdateDose: (dayId: string, doseId: string, field: 'time' | 'ldx' | 'damph', value: string) => void;
+  onUpdateDoseField: (dayId: string, doseId: string, field: string, value: any) => void; // For non-string fields like isFed
  onSortDoses: (dayId: string) => void;
  t: any;
 }
@@ -40,6 +41,7 @@ const DaySchedule: React.FC<DayScheduleProps> = ({
  onAddDose,
  onRemoveDose,
  onUpdateDose,
+  onUpdateDoseField,
  onSortDoses,
  t
 }) => {
@@ -199,8 +201,8 @@ const DaySchedule: React.FC<DayScheduleProps> = ({
          {!collapsedDays.has(day.id) && (
          <CardContent className="space-y-3">
            {/* Dose table header */}
-            <div className="grid grid-cols-[120px_1fr_auto] gap-3 text-sm font-medium text-muted-foreground">
-              <div className="flex items-center gap-2">
+            <div className="grid grid-cols-[100px_1fr_auto_auto] gap-2 text-sm font-medium text-muted-foreground">
+              <div className="flex items-center gap-1">
                <span>{t('time')}</span>
                <Tooltip>
                  <TooltipTrigger asChild>
@@ -227,7 +229,10 @@ const DaySchedule: React.FC<DayScheduleProps> = ({
                </Tooltip>
              </div>
              <div>{t('ldx')} (mg)</div>
-              <div></div>
+              <div className="text-center">
+                <Utensils className="h-4 w-4 inline" />
+              </div>
+              <div className="invisible">-</div>
            </div>

            {/* Dose rows */}
@@ -240,7 +245,7 @@ const DaySchedule: React.FC<DayScheduleProps> = ({
              const isZeroDose = dose.ldx === '0' || dose.ldx === '0.0';

              return (
-                <div key={dose.id} className="grid grid-cols-[120px_1fr_auto] gap-3 items-center">
+                <div key={dose.id} className="grid grid-cols-[120px_1fr_auto_auto] gap-2 items-center">
                  <FormTimeInput
                    value={dose.time}
                    onChange={(value) => onUpdateDose(day.id, dose.id, 'time', value)}
@@ -260,14 +265,22 @@ const DaySchedule: React.FC<DayScheduleProps> = ({
                    errorMessage={t('errorNumberRequired')}
                    warningMessage={t('warningZeroDose')}
                  />
+                  <IconButtonWithTooltip
+                    onClick={() => onUpdateDoseField(day.id, dose.id, 'isFed', !dose.isFed)}
+                    icon={<Utensils className="h-4 w-4" />}
+                    tooltip={dose.isFed ? t('doseWithFood') : t('doseFasted')}
+                    size="sm"
+                    variant={dose.isFed ? "default" : "outline"}
+                    className={`h-9 w-9 p-0 ${dose.isFed ? 'bg-orange-500 hover:bg-orange-600' : ''}`}
+                  />
                  <IconButtonWithTooltip
                    onClick={() => onRemoveDose(day.id, dose.id)}
                    icon={<Trash2 className="h-4 w-4" />}
                    tooltip={t('removeDose')}
                    size="sm"
-                    variant="ghost"
+                    variant="outline"
                    disabled={day.isTemplate && day.doses.length === 1}
-                    className="h-9 w-9 p-0"
+                    className="h-9 w-9 p-0 border-destructive text-destructive hover:bg-destructive hover:text-destructive-foreground disabled:border-muted"
                  />
                </div>
              );
--- a/src/components/settings.tsx
+++ b/src/components/settings.tsx
@@ -43,6 +43,8 @@ const getDefaultsForTranslation = (pkParams: any, therapeuticRange: any, uiSetti
    ldxAbsorptionHalfLife: defaults.pkParams.ldx.absorptionHalfLife,

    // Advanced Settings
+    standardVdValue: defaults.pkParams.advanced.standardVd?.preset === 'adult' ? '377' : defaults.pkParams.advanced.standardVd?.preset === 'child' ? '175' : defaults.pkParams.advanced.standardVd?.customValue || '377',
+    standardVdPreset: defaults.pkParams.advanced.standardVd?.preset || 'adult',
    bodyWeight: defaults.pkParams.advanced.weightBasedVd.bodyWeight,
    tmaxDelay: defaults.pkParams.advanced.foodEffect.tmaxDelay,
    phTendency: defaults.pkParams.advanced.urinePh.phTendency,
@@ -886,8 +888,74 @@ const Settings = ({
              <p className="text-yellow-800 dark:text-yellow-200">{t('advancedSettingsWarning')}</p>
            </div>

+            {/* Standard Volume of Distribution */}
+            <div className="space-y-3">
+              <div className="flex items-center gap-2">
+                <Label className="text-sm font-medium">{t('standardVolumeOfDistribution')}</Label>
+                <Tooltip open={openTooltipId === 'standardVd'} onOpenChange={(open) => setOpenTooltipId(open ? 'standardVd' : null)}>
+                  <TooltipTrigger asChild>
+                    <button
+                      type="button"
+                      onClick={handleTooltipToggle('standardVd')}
+                      onTouchStart={handleTooltipToggle('standardVd')}
+                      className="inline-flex items-center justify-center rounded-sm text-muted-foreground hover:text-foreground focus:outline-none focus:ring-2 focus:ring-ring focus:ring-offset-2"
+                      aria-label={t('standardVdTooltip')}
+                    >
+                      <Info className="h-4 w-4" />
+                    </button>
+                  </TooltipTrigger>
+                  <TooltipContent side={tooltipSide}>
+                    <p className="text-xs max-w-xs">{renderTooltipWithLinks(tWithDefaults(t, 'standardVdTooltip', {
+                      ...defaultsForT,
+                      standardVdValue: pkParams.advanced.standardVd?.preset === 'adult' ? '377' : pkParams.advanced.standardVd?.preset === 'child' ? '175' : pkParams.advanced.standardVd?.customValue || '377',
+                      standardVdPreset: t(`standardVdPreset${pkParams.advanced.standardVd?.preset?.charAt(0).toUpperCase()}${pkParams.advanced.standardVd?.preset?.slice(1)}` || 'standardVdPresetAdult')
+                    }))}</p>
+                  </TooltipContent>
+                </Tooltip>
+              </div>
+              <Select
+                value={pkParams.advanced.standardVd?.preset || 'adult'}
+                onValueChange={(value: 'adult' | 'child' | 'custom') => updateAdvanced('standardVd', 'preset', value)}
+              >
+                <SelectTrigger>
+                  <SelectValue />
+                </SelectTrigger>
+                <SelectContent>
+                  <SelectItem value="adult">{t('standardVdPresetAdult')}</SelectItem>
+                  <SelectItem value="child">{t('standardVdPresetChild')}</SelectItem>
+                  <SelectItem value="custom">{t('standardVdPresetCustom')}</SelectItem>
+                </SelectContent>
+              </Select>
+              {pkParams.advanced.weightBasedVd.enabled && (
+                <div className="ml-0 mt-2 p-2 bg-blue-50 dark:bg-blue-900/20 border border-blue-200 dark:border-blue-800 rounded text-xs text-blue-800 dark:text-blue-200">
+                  ⓘ Weight-based Vd is enabled below. This setting is currently overridden.
+                </div>
+              )}
+              {pkParams.advanced.standardVd?.preset === 'custom' && (
+                <div className="ml-8 mt-2">
+                  <Label className="text-sm font-medium">{t('customVdValue')}</Label>
+                  <FormNumericInput
+                    value={pkParams.advanced.standardVd?.customValue || '377'}
+                    onChange={val => updateAdvanced('standardVd', 'customValue', val)}
+                    increment={10}
+                    min={50}
+                    max={800}
+                    unit="L"
+                    required={true}
+                  />
+                </div>
+              )}
+            </div>
+
+            <Separator className="my-4" />
+
            {/* Weight-Based Vd */}
            <div className="space-y-3">
+              {pkParams.advanced.weightBasedVd.enabled && (
+                <div className="p-2 bg-blue-50 dark:bg-blue-900/20 border border-blue-200 dark:border-blue-800 rounded text-xs text-blue-800 dark:text-blue-200 mb-3">
+                  ⓘ When enabled, this overrides the Standard Vd setting above. Disable to use Standard Vd presets (Adult/Child/Custom).
+                </div>
+              )}
              <div className="flex items-center gap-3">
                <Switch
                  id="weightBasedVdEnabled"
@@ -950,66 +1018,38 @@ const Settings = ({

            <Separator className="my-4" />

-            {/* Food Effect */}
+            <Separator className="my-4" />
+
+            {/* Food Effect Absorption Delay */}
            <div className="space-y-3">
-              <div className="flex items-center gap-3">
-                <Switch
-                  id="foodEffectEnabled"
-                  checked={pkParams.advanced.foodEffect.enabled}
-                  onCheckedChange={checked => updateAdvanced('foodEffect', 'enabled', checked)}
-                />
-                <Label htmlFor="foodEffectEnabled" className="font-medium">
-                  {t('foodEffectEnabled')}
-                </Label>
-                  <Tooltip open={openTooltipId === 'foodEffect'} onOpenChange={(open) => setOpenTooltipId(open ? 'foodEffect' : null)}>
-                    <TooltipTrigger asChild>
-                      <button
-                        type="button"
-                        onClick={handleTooltipToggle('foodEffect')}
-                        onTouchStart={handleTooltipToggle('foodEffect')}
-                        className="inline-flex items-center justify-center rounded-sm text-muted-foreground hover:text-foreground focus:outline-none focus:ring-2 focus:ring-ring focus:ring-offset-2"
-                        aria-label={t('foodEffectTooltip')}
-                      >
-                        <Info className="h-4 w-4" />
-                      </button>
-                    </TooltipTrigger>
-                    <TooltipContent side={tooltipSide}>
-                      <p className="text-xs max-w-xs">{tWithDefaults(t, 'foodEffectTooltip', defaultsForT)}</p>
-                    </TooltipContent>
-                  </Tooltip>
+              <div className="flex items-center gap-2">
+                <Label className="text-sm font-medium">{t('foodEffectDelay')}</Label>
+                <Tooltip open={openTooltipId === 'tmaxDelay'} onOpenChange={(open) => setOpenTooltipId(open ? 'tmaxDelay' : null)}>
+                  <TooltipTrigger asChild>
+                    <button
+                      type="button"
+                      onClick={handleTooltipToggle('tmaxDelay')}
+                      onTouchStart={handleTooltipToggle('tmaxDelay')}
+                      className="inline-flex items-center justify-center rounded-sm text-muted-foreground hover:text-foreground focus:outline-none focus:ring-2 focus:ring-ring focus:ring-offset-2"
+                      aria-label={t('tmaxDelayTooltip')}
+                    >
+                      <Info className="h-4 w-4" />
+                    </button>
+                  </TooltipTrigger>
+                  <TooltipContent side={tooltipSide}>
+                    <p className="text-xs max-w-xs">{renderTooltipWithLinks(tWithDefaults(t, 'tmaxDelayTooltip', defaultsForT))}</p>
+                  </TooltipContent>
+                </Tooltip>
              </div>
-              {pkParams.advanced.foodEffect.enabled && (
-                <div className="ml-8 space-y-2">
-                  <div className="flex items-center gap-2">
-                    <Label className="text-sm font-medium">{t('tmaxDelay')}</Label>
-                      <Tooltip open={openTooltipId === 'tmaxDelay'} onOpenChange={(open) => setOpenTooltipId(open ? 'tmaxDelay' : null)}>
-                    <TooltipTrigger asChild>
-                      <button
-                        type="button"
-                        onClick={handleTooltipToggle('tmaxDelay')}
-                        onTouchStart={handleTooltipToggle('tmaxDelay')}
-                        className="inline-flex items-center justify-center rounded-sm text-muted-foreground hover:text-foreground focus:outline-none focus:ring-2 focus:ring-ring focus:ring-offset-2"
-                        aria-label={t('tmaxDelayTooltip')}
-                      >
-                            <Info className="h-4 w-4" />
-                          </button>
-                        </TooltipTrigger>
-                        <TooltipContent side={tooltipSide}>
-                          <p className="text-xs max-w-xs">{renderTooltipWithLinks(tWithDefaults(t, 'tmaxDelayTooltip', defaultsForT))}</p>
-                        </TooltipContent>
-                      </Tooltip>
-                  </div>
-                  <FormNumericInput
-                    value={pkParams.advanced.foodEffect.tmaxDelay}
-                    onChange={val => updateAdvanced('foodEffect', 'tmaxDelay', val)}
-                    increment={0.1}
-                    min={0}
-                    max={2}
-                    unit={t('tmaxDelayUnit')}
-                    required={true}
-                  />
-                </div>
-              )}
+              <FormNumericInput
+                value={pkParams.advanced.foodEffect.tmaxDelay}
+                onChange={val => updateAdvanced('foodEffect', 'tmaxDelay', val)}
+                increment={0.1}
+                min={0}
+                max={2}
+                unit={t('tmaxDelayUnit')}
+                required={true}
+              />
            </div>

            <Separator className="my-4" />
@@ -1078,6 +1118,108 @@ const Settings = ({

            <Separator className="my-4" />

+            {/* Age Group Selection */}
+            <div className="space-y-3">
+              <div className="flex items-center gap-2">
+                <Label className="text-sm font-medium">{t('ageGroup')}</Label>
+                <Tooltip open={openTooltipId === 'ageGroup'} onOpenChange={(open) => setOpenTooltipId(open ? 'ageGroup' : null)}>
+                  <TooltipTrigger asChild>
+                    <button
+                      type="button"
+                      onClick={handleTooltipToggle('ageGroup')}
+                      onTouchStart={handleTooltipToggle('ageGroup')}
+                      className="inline-flex items-center justify-center rounded-sm text-muted-foreground hover:text-foreground focus:outline-none focus:ring-2 focus:ring-ring focus:ring-offset-2"
+                      aria-label={t('ageGroupTooltip')}
+                    >
+                      <Info className="h-4 w-4" />
+                    </button>
+                  </TooltipTrigger>
+                  <TooltipContent side={tooltipSide}>
+                    <p className="text-xs max-w-xs">{renderTooltipWithLinks(tWithDefaults(t, 'ageGroupTooltip', defaultsForT))}</p>
+                  </TooltipContent>
+                </Tooltip>
+              </div>
+              <Select
+                value={pkParams.advanced.ageGroup?.preset || 'adult'}
+                onValueChange={(value: 'child' | 'adult' | 'custom') => {
+                  updateAdvancedDirect('ageGroup', { preset: value });
+                }}
+              >
+                <SelectTrigger className="w-full">
+                  <SelectValue />
+                </SelectTrigger>
+                <SelectContent>
+                  <SelectItem value="adult">{t('ageGroupAdult')}</SelectItem>
+                  <SelectItem value="child">{t('ageGroupChild')}</SelectItem>
+                  <SelectItem value="custom">{t('ageGroupCustom')}</SelectItem>
+                </SelectContent>
+              </Select>
+            </div>
+
+            <Separator className="my-4" />
+
+            {/* Renal Function */}
+            <div className="space-y-3">
+              <div className="flex items-center gap-3">
+                <Switch
+                  id="renalFunctionEnabled"
+                  checked={pkParams.advanced.renalFunction?.enabled || false}
+                  onCheckedChange={checked => {
+                    updateAdvancedDirect('renalFunction', {
+                      enabled: checked,
+                      severity: pkParams.advanced.renalFunction?.severity || 'normal'
+                    });
+                  }}
+                />
+                <Label htmlFor="renalFunctionEnabled" className="font-medium">
+                  {t('renalFunction')}
+                </Label>
+                <Tooltip open={openTooltipId === 'renalFunction'} onOpenChange={(open) => setOpenTooltipId(open ? 'renalFunction' : null)}>
+                  <TooltipTrigger asChild>
+                    <button
+                      type="button"
+                      onClick={handleTooltipToggle('renalFunction')}
+                      onTouchStart={handleTooltipToggle('renalFunction')}
+                      className="inline-flex items-center justify-center rounded-sm text-muted-foreground hover:text-foreground focus:outline-none focus:ring-2 focus:ring-ring focus:ring-offset-2"
+                      aria-label={t('renalFunctionTooltip')}
+                    >
+                      <Info className="h-4 w-4" />
+                    </button>
+                  </TooltipTrigger>
+                  <TooltipContent side={tooltipSide}>
+                    <p className="text-xs max-w-xs">{renderTooltipWithLinks(tWithDefaults(t, 'renalFunctionTooltip', defaultsForT))}</p>
+                  </TooltipContent>
+                </Tooltip>
+              </div>
+              {(pkParams.advanced.renalFunction?.enabled) && (
+                <div className="ml-8 space-y-2">
+                  <div className="flex items-center gap-2">
+                    <Label className="text-sm font-medium">{t('renalFunctionSeverity')}</Label>
+                  </div>
+                  <Select
+                    value={pkParams.advanced.renalFunction?.severity || 'normal'}
+                    onValueChange={(value: 'normal' | 'mild' | 'severe') => {
+                      updateAdvancedDirect('renalFunction', {
+                        enabled: true,
+                        severity: value
+                      });
+                    }}
+                  >
+                    <SelectTrigger className="w-full">
+                      <SelectValue />
+                    </SelectTrigger>
+                    <SelectContent>
+                      <SelectItem value="normal">{t('renalFunctionNormal')}</SelectItem>
+                      <SelectItem value="mild">{t('renalFunctionMild')}</SelectItem>
+                      <SelectItem value="severe">{t('renalFunctionSevere')}</SelectItem>
+                    </SelectContent>
+                  </Select>
+                </div>
+              )}
+            </div>
+
+            <Separator className="my-4" />
+
            {/* Oral Bioavailability */}
            <div className="space-y-2">
              <div className="flex items-center gap-2">
--- a/src/components/simulation-chart.tsx
+++ b/src/components/simulation-chart.tsx
@@ -209,12 +209,10 @@ const chartDomain = React.useMemo(() => {
    // User set yAxisMax explicitly - use it as-is without padding
    domainMax = numMax;
  } else if (dataMax !== -Infinity) { // data exists
-    // No padding needed since it seems to be added automatically by Recharts
-    // // Auto mode: add 5% padding above
-    // const range = dataMax - dataMin;
-    // const padding = range * 0.05;
-    // domainMax = dataMax + padding;
-    domainMax = dataMax;
+    // Auto mode: add 5% padding above
+    const range = dataMax - dataMin;
+    const padding = range * 0.05;
+    domainMax = dataMax + padding;
  } else { // no data
    domainMax = 100;
  }
--- a/src/constants/defaults.ts
+++ b/src/constants/defaults.ts
@@ -26,7 +26,7 @@ const versionInfo = versionJsonDefault && Object.keys(versionJsonDefault).length
      gitDate: 'unknown',
    };

-export const LOCAL_STORAGE_KEY = 'medPlanAssistantState_v7';
+export const LOCAL_STORAGE_KEY = 'medPlanAssistantState_v8'; // Incremented for ageGroup + renalFunction fields
 export const PROJECT_REPOSITORY_URL = 'https://git.11001001.org/cbaoth/med-plan-assistant';
 export const APP_VERSION = versionInfo.version;
 export const BUILD_INFO = versionInfo;
@@ -39,11 +39,23 @@ export const DEFAULT_F_ORAL = 0.96;

 // Type definitions
 export interface AdvancedSettings {
+  standardVd: { preset: 'adult' | 'child' | 'custom'; customValue: string }; // Volume of distribution (L)
  weightBasedVd: { enabled: boolean; bodyWeight: string }; // kg
  foodEffect: { enabled: boolean; tmaxDelay: string }; // hours
  urinePh: { enabled: boolean; phTendency: string }; // 5.5-8.0 range
  fOral: string; // bioavailability fraction
  steadyStateDays: string; // days of medication history to simulate
+  // Age-specific pharmacokinetics (Research Section 5.2)
+  // Children (6-12y) have faster elimination: t½ ~9h vs adult ~11h
+  ageGroup?: {
+    preset: 'child' | 'adult' | 'custom';
+  };
+  // Renal function effects (Research Section 8.2, FDA label 8.6)
+  // Severe impairment extends half-life by ~50% (11h → 16.5h)
+  renalFunction?: {
+    enabled: boolean;
+    severity: 'normal' | 'mild' | 'severe';
+  };
 }

 export interface PkParams {
@@ -57,6 +69,7 @@ export interface DayDose {
  time: string;
  ldx: string;
  damph?: string; // Optional, kept for backwards compatibility but not used in UI
+  isFed?: boolean; // Optional: indicates if dose is taken with food (delays absorption ~1h)
 }

 export interface DayGroup {
@@ -121,9 +134,10 @@ export const getDefaultState = (): AppState => ({
    damph: { halfLife: '11' },
    ldx: {
      halfLife: '0.8',
-      absorptionHalfLife: '0.9' // changed from 1.5, better reflects ~1h Tmax
+      absorptionHalfLife: '0.7' // Updated from 0.9 for better ~1h Tmax of prodrug
    },
    advanced: {
+      standardVd: { preset: 'adult', customValue: '377' }, // Adult: 377L (Roberts 2015), Child: ~150-200L
      weightBasedVd: { enabled: false, bodyWeight: '70' }, // kg, adult average
      foodEffect: { enabled: false, tmaxDelay: '1.0' }, // hours delay
      urinePh: { enabled: false, phTendency: '6.0' }, // pH scale (5.5-8.0)
@@ -144,7 +158,7 @@ export const getDefaultState = (): AppState => ({
    }
  ],
  steadyStateConfig: { daysOnMedication: '7' }, // kept for backwards compatibility, now sourced from pkParams.advanced
-  therapeuticRange: { min: '5', max: '25' }, // widened from 10.5-11.5 to general adult range
+  therapeuticRange: { min: '', max: '' }, // Empty by default - users should personalize based on their response
  doseIncrement: '2.5',
  uiSettings: {
    showDayTimeOnXAxis: '24h',
@@ -154,7 +168,7 @@ export const getDefaultState = (): AppState => ({
    yAxisMax: '',
    simulationDays: '5',
    displayedDays: '2',
-    showTherapeuticRange: true,
+    showTherapeuticRange: false,
    steadyStateDaysEnabled: true,
    stickyChart: false,
  }
--- a/src/hooks/useAppState.ts
+++ b/src/hooks/useAppState.ts
@@ -199,6 +199,25 @@ export const useAppState = () => {
    }));
  };

+  // More flexible update function for non-string fields (e.g., isFed boolean)
+  const updateDoseFieldInDay = (dayId: string, doseId: string, field: string, value: any) => {
+    setAppState(prev => ({
+      ...prev,
+      days: prev.days.map(day => {
+        if (day.id !== dayId) return day;
+
+        const updatedDoses = day.doses.map(dose =>
+          dose.id === doseId ? { ...dose, [field]: value } : dose
+        );
+
+        return {
+          ...day,
+          doses: updatedDoses
+        };
+      })
+    }));
+  };
+
  const sortDosesInDay = (dayId: string) => {
    setAppState(prev => ({
      ...prev,
@@ -238,6 +257,7 @@ export const useAppState = () => {
    addDoseToDay,
    removeDoseFromDay,
    updateDoseInDay,
+    updateDoseFieldInDay,
    sortDosesInDay,
    handleReset
  };
--- a/src/locales/de.ts
+++ b/src/locales/de.ts
@@ -24,6 +24,8 @@ export const de = {
  afternoon: "Nachmittags",
  evening: "Abends",
  night: "Nachts",
+  doseWithFood: "Mit Nahrung eingenommen (verzögert Absorption ~1h)",
+  doseFasted: "Nüchtern eingenommen (normale Absorption)",

  // Deviations
  deviationsFromPlan: "Abweichungen vom Plan",
@@ -71,6 +73,12 @@ export const de = {
  pharmacokineticsSettings: "Pharmakokinetik-Einstellungen",
  advancedSettings: "Erweiterte Einstellungen",
  advancedSettingsWarning: "⚠️ Diese Parameter beeinflussen die Simulationsgenauigkeit und können von Bevölkerungsdurchschnitten abweichen. Nur anpassen, wenn spezifische klinische Daten oder Forschungsreferenzen vorliegen.",
+  standardVolumeOfDistribution: "Verteilungsvolumen (Vd)",
+  standardVdTooltip: "Definiert wie sich der Wirkstoff im Körper verteilt. Erwachsene: 377L (Roberts 2015), Kinder: ~150-200L. Beeinflusst alle Konzentrationsberechnungen. Nur für pädiatrische oder spezialisierte Simulationen ändern. Standard: {{standardVdValue}}L ({{standardVdPreset}}).",
+  standardVdPresetAdult: "Erwachsene (377L)",
+  standardVdPresetChild: "Kinder (175L)",
+  standardVdPresetCustom: "Benutzerdefiniert",
+  customVdValue: "Benutzerdefiniertes Vd (L)",
  xAxisTimeFormat: "Zeitformat",
  xAxisFormatContinuous: "Fortlaufend",
  xAxisFormatContinuousDesc: "Endlose Sequenz (0h, 6h, 12h...)",
@@ -96,7 +104,7 @@ export const de = {
  yAxisRangeAutoButtonTitle: "Bereich automatisch anhand des Datenbereichs bestimmen",
  auto: "Auto",
  therapeuticRange: "Therapeutischer Bereich",
-  therapeuticRangeTooltip: "Referenzkonzentrationen für Medikamentenwirksamkeit. Typischer Bereich für Erwachsene: 5-25 ng/mL. Individuelle therapeutische Fenster variieren erheblich. Standard: {{therapeuticRangeMin}}-{{therapeuticRangeMax}} ng/mL. Konsultiere deinen Arzt.",
+  therapeuticRangeTooltip: "Personalisierte Konzentrationsziele basierend auf DEINER individuellen Reaktion. Setze diese nachdem du beobachtet hast, welche Werte Symptomkontrolle vs. Nebenwirkungen bieten. Referenzbereiche (stark variabel): Erwachsene ~10-80 ng/mL, Kinder ~20-120 ng/mL (aufgrund geringeren Körpergewichts/Vd). Leer lassen wenn unsicher. Konsultiere deinen Arzt.",
  dAmphetamineParameters: "d-Amphetamin Parameter",
  halfLife: "Eliminations-Halbwertszeit",
  halfLifeTooltip: "Zeit bis der Körper die Hälfte des d-Amphetamins aus dem Blut ausscheidet. Beeinflusst durch Urin-pH: sauer (<6) → 7-9h, neutral (6-7,5) → 10-12h, alkalisch (>7,5) → 13-15h. Siehe [therapeutische Referenzbereiche](https://www.thieme-connect.com/products/ejournals/pdf/10.1055/a-2689-4911.pdf). Standard: {{damphHalfLife}}h.",
@@ -115,9 +123,10 @@ export const de = {
  bodyWeightUnit: "kg",

  foodEffectEnabled: "Mit Mahlzeit eingenommen",
-  foodEffectTooltip: "Fettreiche Mahlzeiten verzögern die Absorption ohne Gesamtaufnahme zu ändern. Verlangsamt Wirkungseintritt (~1h Verzögerung). Bei Deaktivierung: Nüchterner Zustand.",
-  tmaxDelay: "Absorptionsverzögerung",
-  tmaxDelayTooltip: "Wie viel die Mahlzeit die Absorption verzögert (Tmax-Verschiebung). Siehe [Nahrungseffekt-Studie](https://pmc.ncbi.nlm.nih.gov/articles/PMC4823324/) von Ermer et al. Typisch: 1,0h für fettreiche Mahlzeit. Standard: {{tmaxDelay}}h.",
+  foodEffectDelay: "Nahrungseffekt-Verzögerung",
+  foodEffectTooltip: "Fettreiche Mahlzeiten verzögern die Absorption ohne die Gesamtaufnahme zu ändern. Verlangsamt Wirkungseintritt (~1h Verzögerung). Deaktiviert nimmt nüchternen Zustand an.",
+  tmaxDelay: "Absorptions-Verzögerung",
+  tmaxDelayTooltip: "Zeitverzögerung bei Einnahme mit fettreicher Mahlzeit. Wird durch Einzel-Dosis Nahrungsschalter (🍴 Symbol) im Zeitplan angewendet. Forschung zeigt ~1h Verzögerung ohne Spitzenreduktion. Siehe [Studie](https://pmc.ncbi.nlm.nih.gov/articles/PMC4823324/). Standard: {{tmaxDelay}}h.",
  tmaxDelayUnit: "h",

  urinePHTendency: "Urin-pH-Effekte",
@@ -133,6 +142,21 @@ export const de = {
  steadyStateDays: "Medikationshistorie",
  steadyStateDaysTooltip: "Anzahl vorheriger Tage stabiler Medikamentendosis zur Simulation der Akkumulation/Steady-State. 0 setzen für \"erster Tag ohne Vorgeschichte.\" Standard: {{steadyStateDays}} Tage. Max: 7.",

+  // Age-specific pharmacokinetics
+  ageGroup: "Altersgruppe",
+  ageGroupTooltip: "Pädiatrische Personen (6-12 J.) zeigen schnellere d-Amphetamin-Elimination (t½ ~9h) verglichen mit Erwachsenen (~11h) aufgrund höherer gewichtsnormalisierter Stoffwechselrate. Siehe [Forschungsdokument](https://git.11001001.org/cbaoth/med-plan-assistant/src/branch/main/docs/2026-01-17_AI-Reseach_SimulatingLDXandD-AmphetaminePlasmaLevels.md#52-pediatric-vs-adult-modeling) Abschnitt 5.2. 'Benutzerdefiniert' wählen, um manuell konfigurierte Halbwertszeit zu verwenden. Standard: Erwachsener.",
+  ageGroupAdult: "Erwachsener (t½ 11h)",
+  ageGroupChild: "Kind 6-12 J. (t½ 9h)",
+  ageGroupCustom: "Benutzerdefiniert (manuelle t½)",
+
+  // Renal function effects
+  renalFunction: "Niereninsuffizienz",
+  renalFunctionTooltip: "Schwere Niereninsuffizienz verlängert d-Amphetamin-Halbwertszeit um ~50% (von 11h auf 16,5h). FDA-Label empfiehlt Dosierungsobergrenzen: 50mg bei schwerer Insuffizienz, 30mg bei Nierenversagen (ESRD). Siehe [FDA-Label Abschnitt 8.6](https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021977s049lbl.pdf) und [Forschungsdokument](https://git.11001001.org/cbaoth/med-plan-assistant/src/branch/main/docs/2026-01-17_AI-Reseach_SimulatingLDXandD-AmphetaminePlasmaLevels.md#82-renal-function) Abschnitt 8.2. Standard: deaktiviert.",
+  renalFunctionSeverity: "Schweregrad der Insuffizienz",
+  renalFunctionNormal: "Normal (keine Anpassung)",
+  renalFunctionMild: "Leicht (keine Anpassung)",
+  renalFunctionSevere: "Schwer (t½ +50%)",
+
  resetAllSettings: "Alle Einstellungen zurücksetzen",
  resetDiagramSettings: "Diagramm-Einstellungen zurücksetzen",
  resetPharmacokineticSettings: "Pharmakokinetik-Einstellungen zurücksetzen",
--- a/src/locales/en.ts
+++ b/src/locales/en.ts
@@ -24,6 +24,8 @@ export const en = {
  afternoon: "Afternoon",
  evening: "Evening",
  night: "Night",
+  doseWithFood: "Taken with food (delays absorption ~1h)",
+  doseFasted: "Taken fasted (normal absorption)",

  // Deviations
  deviationsFromPlan: "Deviations from Plan",
@@ -70,6 +72,12 @@ export const en = {
  pharmacokineticsSettings: "Pharmacokinetics Settings",
  advancedSettings: "Advanced Settings",
  advancedSettingsWarning: "⚠️ These parameters affect simulation accuracy and may deviate from population averages. Adjust only if you have specific clinical data or research references.",
+  standardVolumeOfDistribution: "Volume of Distribution (Vd)",
+  standardVdTooltip: "Defines how drug disperses in body. Adult: 377L (Roberts 2015), Child: ~150-200L. Affects all concentration calculations. Change only for pediatric or specialized simulations. Default: {{standardVdValue}}L ({{standardVdPreset}}).",
+  standardVdPresetAdult: "Adult (377L)",
+  standardVdPresetChild: "Child (175L)",
+  standardVdPresetCustom: "Custom",
+  customVdValue: "Custom Vd (L)",
  xAxisTimeFormat: "Time Format",
  xAxisFormatContinuous: "Continuous",
  xAxisFormatContinuousDesc: "Endless sequence (0h, 6h, 12h...)",
@@ -94,7 +102,7 @@ export const en = {
  yAxisRangeAutoButtonTitle: "Determine range automatically based on data range",
  auto: "Auto",
  therapeuticRange: "Therapeutic Range",
-  therapeuticRangeTooltip: "Reference concentrations for medication efficacy. Typical adult range: 5-25 ng/mL. Individual therapeutic windows vary significantly. Default: {{therapeuticRangeMin}}-{{therapeuticRangeMax}} ng/mL. Consult your physician.",
+  therapeuticRangeTooltip: "Personalized concentration targets based on YOUR individual response. Set these after observing which levels provide symptom control vs. side effects. Reference ranges (highly variable): Adults ~10-80 ng/mL, Children ~20-120 ng/mL (due to lower body weight/Vd). Leave empty if unsure. Consult your physician.",
  dAmphetamineParameters: "d-Amphetamine Parameters",
  halfLife: "Elimination Half-life",
  halfLifeTooltip: "Time for body to clear half the d-amphetamine from blood. Affected by urine pH: acidic (<6) → 7-9h, neutral (6-7.5) → 10-12h, alkaline (>7.5) → 13-15h. See [therapeutic reference ranges](https://www.thieme-connect.com/products/ejournals/pdf/10.1055/a-2689-4911.pdf). Default: {{damphHalfLife}}h.",
@@ -113,9 +121,10 @@ export const en = {
  bodyWeightUnit: "kg",

  foodEffectEnabled: "Taken With Meal",
+  foodEffectDelay: "Food Effect Delay",
  foodEffectTooltip: "High-fat meals delay absorption without changing total exposure. Slows onset of effects (~1h delay). When disabled, assumes fasted state.",
  tmaxDelay: "Absorption Delay",
-  tmaxDelayTooltip: "How much the meal delays absorption (Tmax shift). See [food effect study](https://pmc.ncbi.nlm.nih.gov/articles/PMC4823324/) by Ermer et al. Typical: 1.0h for high-fat meal. Default: {{tmaxDelay}}h.",
+  tmaxDelayTooltip: "Time delay when dose is taken with high-fat meal. Applied using per-dose food toggles (🍴 icon) in schedule. Research shows ~1h delay without peak reduction. See [study](https://pmc.ncbi.nlm.nih.gov/articles/PMC4823324/). Default: {{tmaxDelay}}h.",
  tmaxDelayUnit: "h",

  urinePHTendency: "Urine pH Effects",
@@ -131,6 +140,21 @@ export const en = {
  steadyStateDays: "Medication History",
  steadyStateDaysTooltip: "Number of prior days on stable medication dose to simulate accumulation/steady-state. Set 0 for \"first day from scratch.\" Default: {{steadyStateDays}} days. Max: 7.",

+  // Age-specific pharmacokinetics
+  ageGroup: "Age Group",
+  ageGroupTooltip: "Pediatric subjects (6-12y) exhibit faster d-amphetamine elimination (t½ ~9h) compared to adults (~11h) due to higher weight-normalized metabolic rate. See [research document](https://git.11001001.org/cbaoth/med-plan-assistant/src/branch/main/docs/2026-01-17_AI-Reseach_SimulatingLDXandD-AmphetaminePlasmaLevels.md#52-pediatric-vs-adult-modeling) Section 5.2. Select 'custom' to use your manually configured half-life. Default: adult.",
+  ageGroupAdult: "Adult (t½ 11h)",
+  ageGroupChild: "Child 6-12y (t½ 9h)",
+  ageGroupCustom: "Custom (use manual t½)",
+
+  // Renal function effects
+  renalFunction: "Renal Impairment",
+  renalFunctionTooltip: "Severe renal impairment extends d-amphetamine half-life by ~50% (from 11h to 16.5h). FDA label recommends dose caps: 50mg for severe impairment, 30mg for ESRD. See [FDA Label Section 8.6](https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021977s049lbl.pdf) and [research document](https://git.11001001.org/cbaoth/med-plan-assistant/src/branch/main/docs/2026-01-17_AI-Reseach_SimulatingLDXandD-AmphetaminePlasmaLevels.md#82-renal-function) Section 8.2. Default: disabled.",
+  renalFunctionSeverity: "Impairment Severity",
+  renalFunctionNormal: "Normal (no adjustment)",
+  renalFunctionMild: "Mild (no adjustment)",
+  renalFunctionSevere: "Severe (t½ +50%)",
+
  resetAllSettings: "Reset All Settings",
  resetDiagramSettings: "Reset Diagram Settings",
  resetPharmacokineticSettings: "Reset Pharmacokinetic Settings",
--- a/src/utils/calculations.ts
+++ b/src/utils/calculations.ts
@@ -17,6 +17,7 @@ interface ProcessedDose {
  timeMinutes: number;
  ldx: number;
  damph: number;
+  isFed?: boolean; // Optional: indicates if dose was taken with food
 }

 export const calculateCombinedProfile = (
@@ -50,7 +51,8 @@ export const calculateCombinedProfile = (
          allDoses.push({
            timeMinutes: timeToMinutes(dose.time) + dayOffsetMinutes,
            ldx: ldxNum,
-            damph: 0 // d-amph is calculated from LDX conversion, not administered directly
+            damph: 0, // d-amph is calculated from LDX conversion, not administered directly
+            isFed: dose.isFed // Pass through per-dose food effect flag
          });
        }
      });
@@ -66,7 +68,8 @@ export const calculateCombinedProfile = (
        allDoses.push({
          timeMinutes: timeToMinutes(dose.time) + dayOffsetMinutes,
          ldx: ldxNum,
-          damph: 0 // d-amph is calculated from LDX conversion, not administered directly
+          damph: 0, // d-amph is calculated from LDX conversion, not administered directly
+          isFed: dose.isFed // Pass through per-dose food effect flag
        });
      }
    });
@@ -81,11 +84,12 @@ export const calculateCombinedProfile = (
      const timeSinceDoseHours = t - dose.timeMinutes / 60;

      if (timeSinceDoseHours >= 0) {
-        // Calculate LDX contribution
+        // Calculate LDX contribution with per-dose food effect
        const ldxConcentrations = calculateSingleDoseConcentration(
          String(dose.ldx),
          timeSinceDoseHours,
-          pkParams
+          pkParams,
+          dose.isFed // Pass per-dose food flag
        );
        totalLdx += ldxConcentrations.ldx;
        totalDamph += ldxConcentrations.damph;
--- a/src/utils/pharmacokinetics.ts
+++ b/src/utils/pharmacokinetics.ts
@@ -5,6 +5,12 @@
 * and its active metabolite dextroamphetamine (d-amph). Uses first-order
 * absorption and elimination kinetics with optional advanced modifiers.
 *
+ * RESEARCH REFERENCES:
+ * - Roberts et al. (2015): Population PK parameters for d-amphetamine
+ * - PMC4823324 (Ermer et al.): Meta-analysis of LDX pharmacokinetics
+ * - FDA NDA 021-977: Clinical pharmacology of lisdexamfetamine
+ * - AI Research Document (2026-01-17): Sections 3.2, 5.2, 8.2
+ *
 * @author Andreas Weyer
 * @license MIT
 */
@@ -16,26 +22,91 @@ interface ConcentrationResult {
  damph: number;
 }

-// Standard adult volume of distribution (Roberts et al. 2015): 377 L
-const STANDARD_VD_ADULT = 377.0;
+/**
+ * Volume of Distribution Constants
+ *
+ * LDX Apparent Vd (~710L): Due to rapid RBC hydrolysis, intact LDX exhibits a large
+ * apparent Vd. The prodrug is cleared so quickly from plasma that it creates a
+ * "metabolic sink" effect, requiring a mathematically larger Vd to match observed
+ * low peak concentrations (~58 ng/mL for 70mg dose).
+ *
+ * d-Amphetamine Vd (377L adult, 175L child): Standard central Vd from population PK.
+ * Scales with body weight (~5.4 L/kg).
+ *
+ * Ratio: LDX Vd / d-Amph Vd ≈ 1.9 ensures proper concentration crossover
+ * (LDX peaks early but lower than d-amph, as observed clinically).
+ *
+ * Reference: AI Research Document Section 3.2 "Quantitative Derivation of Apparent Vd"
+ */
+const STANDARD_VD_DAMPH_ADULT = 377.0; // d-amphetamine Vd (adult)
+const STANDARD_VD_DAMPH_CHILD = 175.0; // d-amphetamine Vd (pediatric, 6-12y)
+const LDX_VD_SCALING_FACTOR = 1.9; // LDX apparent Vd is ~1.9x d-amphetamine Vd
+
+/**
+ * Age-Specific Elimination Half-Life Constants
+ *
+ * Pediatric subjects (6-12y) exhibit faster d-amphetamine clearance due to
+ * higher weight-normalized metabolic rate. Adult values represent population mean.
+ *
+ * Reference: AI Research Document Section 5.2 "Pediatric vs. Adult Modeling"
+ */
+const DAMPH_T_HALF_ADULT = 11.0; // hours
+const DAMPH_T_HALF_CHILD = 9.0; // hours
+
+/**
+ * Renal Function Modifiers
+ *
+ * Severe impairment can extend half-life by ~50% (from 11h to ~16.5h).
+ * ESRD (end-stage renal disease) can extend to 20h+.
+ *
+ * Reference: AI Research Document Section 8.2, FDA label Section 8.6
+ */
+const RENAL_SEVERE_FACTOR = 1.5; // 50% slower elimination

 // Pharmacokinetic calculations
 export const calculateSingleDoseConcentration = (
  dose: string,
  timeSinceDoseHours: number,
-  pkParams: PkParams
+  pkParams: PkParams,
+  isFed?: boolean // Optional: per-dose food effect override (true = with food, false/undefined = fasted or use global setting)
 ): ConcentrationResult => {
  const numDose = parseFloat(dose) || 0;
  if (timeSinceDoseHours < 0 || numDose <= 0) return { ldx: 0, damph: 0 };

-  // Extract base parameters
+  // ===== EXTRACT BASE PARAMETERS =====
  const absorptionHalfLife = parseFloat(pkParams.ldx.absorptionHalfLife);
  const conversionHalfLife = parseFloat(pkParams.ldx.halfLife);
-  const damphHalfLife = parseFloat(pkParams.damph.halfLife);
+
+  // Use base d-amph half-life from config (default: 11h adult)
+  let damphHalfLife = parseFloat(pkParams.damph.halfLife);
+
+  // ===== APPLY AGE-SPECIFIC ELIMINATION (Research Section 5.2) =====
+  // Children metabolize d-amphetamine faster due to higher weight-normalized metabolic rate
+  // This modifier takes precedence over base half-life if age group is explicitly set
+  if (pkParams.advanced.ageGroup) {
+    if (pkParams.advanced.ageGroup.preset === 'child') {
+      damphHalfLife = DAMPH_T_HALF_CHILD; // 9h
+    } else if (pkParams.advanced.ageGroup.preset === 'adult') {
+      damphHalfLife = DAMPH_T_HALF_ADULT; // 11h
+    }
+    // 'custom' preset uses the base pkParams.damph.halfLife value
+  }
+
+  // ===== APPLY RENAL FUNCTION MODIFIER (Research Section 8.2, FDA label Section 8.6) =====
+  // Renal impairment significantly extends d-amphetamine elimination half-life
+  // Severe: ~50% slower (11h → 16.5h), ESRD: up to 20h+
+  if (pkParams.advanced.renalFunction && pkParams.advanced.renalFunction.enabled) {
+    const impairment = pkParams.advanced.renalFunction.severity;
+    if (impairment === 'severe') {
+      damphHalfLife *= RENAL_SEVERE_FACTOR; // ~16.5h for adult
+    }
+    // 'normal' and 'mild' severity: no adjustment (adequate renal clearance)
+  }

  // Extract advanced parameters
  const fOral = parseFloat(pkParams.advanced.fOral) || DEFAULT_F_ORAL;
-  const foodEnabled = pkParams.advanced.foodEffect.enabled;
+  // Per-dose food effect takes precedence over global setting
+  const foodEnabled = isFed !== undefined ? isFed : pkParams.advanced.foodEffect.enabled;
  const tmaxDelay = foodEnabled ? parseFloat(pkParams.advanced.foodEffect.tmaxDelay) : 0;
  const urinePHEnabled = pkParams.advanced.urinePh.enabled;
  const phTendency = urinePHEnabled ? parseFloat(pkParams.advanced.urinePh.phTendency) : 6.0;
@@ -47,9 +118,11 @@ export const calculateSingleDoseConcentration = (
    return { ldx: 0, damph: 0 };
  }

-  // Apply food effect: high-fat meal delays absorption by slowing rate (~+1h to Tmax)
-  // Approximate by increasing absorption half-life proportionally
-  const adjustedAbsorptionHL = absorptionHalfLife * (1 + (tmaxDelay / 1.5));
+  // Apply food effect: high-fat meal delays absorption by ~1h without changing Cmax
+  // Research shows Tmax delay but no significant AUC/Cmax reduction (Krishnan & Zhang)
+  // Shift absorption start time rightward instead of modifying rate constants
+  const adjustedTime = Math.max(0, timeSinceDoseHours - tmaxDelay);
+  const calculationTime = adjustedTime; // Use delayed time for all kinetic calculations

  // Apply urine pH effect on elimination half-life
  // pH < 6: acidic (faster elimination, HL ~7-9h)
@@ -68,43 +141,77 @@ export const calculateSingleDoseConcentration = (
  }

  // Calculate rate constants
-  const ka_ldx = Math.log(2) / adjustedAbsorptionHL;
+  const ka_ldx = Math.log(2) / absorptionHalfLife;
  const k_conv = Math.log(2) / conversionHalfLife;
  const ke_damph = Math.log(2) / adjustedDamphHL;

  // Apply stoichiometric conversion and bioavailability
  const effectiveDose = numDose * LDX_TO_DAMPH_SALT_FACTOR * fOral;

-  // Calculate LDX concentration (prodrug)
-  let ldxConcentration = 0;
+  // ===== COMPARTMENTAL MODELING (Research Section 6.2) =====
+
+  // LDX CONCENTRATION (Prodrug compartment)
+  // Uses LDX-SPECIFIC APPARENT Vd = 710L (Research Section 3.2, 3.3)
+  // This larger Vd ensures LDX peak (~58 ng/mL for 70mg dose) is LOWER than
+  // d-amph peak (~80 ng/mL), reproducing the clinical "crossover" phenomenon
+  let ldxAmount = 0;
  if (Math.abs(ka_ldx - k_conv) > 0.0001) {
-    ldxConcentration = (numDose * ka_ldx / (ka_ldx - k_conv)) *
-      (Math.exp(-k_conv * timeSinceDoseHours) - Math.exp(-ka_ldx * timeSinceDoseHours));
+    ldxAmount = (numDose * ka_ldx / (ka_ldx - k_conv)) *
+      (Math.exp(-k_conv * calculationTime) - Math.exp(-ka_ldx * calculationTime));
  }

-  // Calculate d-amphetamine concentration (active metabolite)
-  let damphConcentration = 0;
+  // Calculate d-amphetamine concentration (active metabolite) - amount in compartment (mg)
+  let damphAmount = 0;
  if (Math.abs(ka_ldx - ke_damph) > 0.0001 &&
      Math.abs(k_conv - ke_damph) > 0.0001 &&
      Math.abs(ka_ldx - k_conv) > 0.0001) {
-    const term1 = Math.exp(-ke_damph * timeSinceDoseHours) / ((ka_ldx - ke_damph) * (k_conv - ke_damph));
-    const term2 = Math.exp(-k_conv * timeSinceDoseHours) / ((ka_ldx - k_conv) * (ke_damph - k_conv));
-    const term3 = Math.exp(-ka_ldx * timeSinceDoseHours) / ((k_conv - ka_ldx) * (ke_damph - ka_ldx));
-    damphConcentration = effectiveDose * ka_ldx * k_conv * (term1 + term2 + term3);
+    const term1 = Math.exp(-ke_damph * calculationTime) / ((ka_ldx - ke_damph) * (k_conv - ke_damph));
+    const term2 = Math.exp(-k_conv * calculationTime) / ((ka_ldx - k_conv) * (ke_damph - k_conv));
+    const term3 = Math.exp(-ka_ldx * calculationTime) / ((k_conv - ka_ldx) * (ke_damph - ka_ldx));
+    damphAmount = effectiveDose * ka_ldx * k_conv * (term1 + term2 + term3);
  }

-  // Apply weight-based Vd scaling if enabled
-  // Standard adult Vd = 377 L; weight-normalized ~5.4 L/kg
-  // Concentration inversely proportional to Vd: C = Amount / Vd
-  if (pkParams.advanced.weightBasedVd.enabled) {
-    const bodyWeight = parseFloat(pkParams.advanced.weightBasedVd.bodyWeight);
-    if (!isNaN(bodyWeight) && bodyWeight > 0) {
-      const weightBasedVd = bodyWeight * 5.4; // L/kg factor from literature
-      const scalingFactor = STANDARD_VD_ADULT / weightBasedVd;
-      damphConcentration *= scalingFactor;
-      ldxConcentration *= scalingFactor;
+  // ===== DETERMINE VOLUME OF DISTRIBUTION (Research Section 8.1) =====
+  // Priority: Weight-based Vd > Age/preset Vd > Standard adult Vd (377L)
+  let baseVd_damph = STANDARD_VD_DAMPH_ADULT; // Default fallback for d-amphetamine
+
+  // Age-based or custom Vd preset
+  if (pkParams.advanced.standardVd) {
+    if (pkParams.advanced.standardVd.preset === 'adult') {
+      baseVd_damph = STANDARD_VD_DAMPH_ADULT; // 377L
+    } else if (pkParams.advanced.standardVd.preset === 'child') {
+      baseVd_damph = STANDARD_VD_DAMPH_CHILD; // 175L (~5.4 L/kg for 32kg pediatric average)
+    } else if (pkParams.advanced.standardVd.preset === 'custom') {
+      const customVd = parseFloat(pkParams.advanced.standardVd.customValue);
+      if (!isNaN(customVd) && customVd > 0) {
+        baseVd_damph = customVd;
+      }
    }
  }

+  // Weight-based Vd scaling (OVERRIDES preset if enabled)
+  // Research Section 8.1: Vd_damph ≈ 5.4 L/kg body weight
+  // Lighter person → smaller Vd → higher concentration
+  // Heavier person → larger Vd → lower concentration
+  let effectiveVd_damph = baseVd_damph;
+  if (pkParams.advanced.weightBasedVd.enabled) {
+    const bodyWeight = parseFloat(pkParams.advanced.weightBasedVd.bodyWeight);
+    if (!isNaN(bodyWeight) && bodyWeight > 0) {
+      effectiveVd_damph = bodyWeight * 5.4; // L/kg factor from literature
+    }
+  }
+
+  // LDX apparent Vd (Research Section 3.2, 3.3)
+  // Uses fixed 1.9x scaling factor relative to d-amph Vd
+  // This ratio is derived from clinical AUC data and ensures proper peak height relationship
+  // Clinical validation: 70mg dose → LDX peak ~58 ng/mL, d-amph peak ~80 ng/mL
+  const effectiveVd_ldx = effectiveVd_damph * LDX_VD_SCALING_FACTOR; // ~710L for 70kg adult
+
+  // ===== CONVERT AMOUNTS TO PLASMA CONCENTRATIONS =====
+  // Formula: C(ng/mL) = (Amount_mg / Vd_L) × 1000
+  // This is the critical step - without 1000x scaling factor, concentrations are too low
+  let ldxConcentration = (ldxAmount / effectiveVd_ldx) * 1000;
+  let damphConcentration = (damphAmount / effectiveVd_damph) * 1000;
+
  return { ldx: Math.max(0, ldxConcentration), damph: Math.max(0, damphConcentration) };
 };