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## Adenomyosis (자궁선근증) — QSP / PK-PD Model

## ============================================================================

## Disease : Adenomyosis (uterine adenomyosis, diffuse + focal)

## Authors : Generated by Claude Code Routine (QSP Disease Model Library)

## Engine : mrgsolve (>=1.5)

## Scope : 23 ODE compartments — drug PK (relugolix, elagolix, leuprolide,

## dienogest, LNG-IUS local + systemic, letrozole, NSAID, TXA) +

## HPO axis (GnRH-FSH-LH-E2) + local lesion biology (aromatase,

## local E2, COX-2/PGE2, TGF-β/fibrosis, VEGF, NGF) +

## clinical readouts (JZ thickness, PBAC HMB score, dysmenorrhea

## VAS, EHP-30 QoL, hemoglobin, BMD).

## Time : days (study horizon 0 – 720 d, default 365 d / 12 cycles)

## Units : dose in mg; concentration in mg/L = µg/mL; hormones in pg/mL;

## lesion/biomarker scores in study-specific units (see comments).

## Scenarios: 10 prebuilt — see ADENO_simulate_scenarios() at bottom.

## Anchors : SPIRIT-1/2 (relugolix-CT, endo) Giudice 2022 Lancet 399:2267;

## ELARIS EM-I/II (elagolix) Taylor 2017 NEJM 377:28;

## KIM-ADENO (dienogest 2 mg) Osuga 2017 Fertil Steril 108:673;

## Sheng 2009 Contraception 79:189 (LNG-IUS adenomyosis);

## Pierce 1999 J Clin Pharmacol 39:1228 (add-back BMD);

## Kim 2013 Reprod Sci 20:546 (letrozole adenomyosis);

## Lethaby NICE NG88 (TXA HMB).

## Disclaimer: For research / education / hypothesis generation only.

## Not a substitute for clinical judgment or regulatory filings.

## ============================================================================

[PROB]

QSP model for Adenomyosis covering hormonal, anti-inflammatory, and anti-

fibrinolytic interventions with mechanistic links to junctional-zone biology

and the canonical clinical endpoints (HMB / dysmenorrhea / QoL / JZ thickness).

[PLUGIN] Rcpp

[PARAM] @annotated

//--- Patient

AGE : 35 : age (years)

WT : 65 : body weight (kg)

BMI : 24 : body mass index

PARITY : 1 : parity (0..4+)

ETHN : 1 : ethnicity (1=East-Asian,2=Caucasian,3=African)

BASE_JZ : 12 : baseline junctional-zone thickness (mm)

BASE_PBAC : 250 : baseline PBAC (>100 = HMB; severe ~250)

BASE_VAS : 7 : baseline dysmenorrhea VAS (0-10)

BASE_HB : 11.0 : baseline hemoglobin (g/dL)

BASE_BMD : 1.05 : baseline lumbar BMD (g/cm^2)

ADENO_SEV : 2 : severity (1=mild,2=moderate,3=severe)

//--- Dosing flags (selected by amt and cmt)

// amounts come through EV() events; PK params below

//--- Relugolix PK (40 mg PO QD; F=11.6%; Vd~3700 L; CL~9.4 L/h) Markham 2019

KA_REL : 1.8 : absorption rate (1/day)

F_REL : 0.116 : oral bioavailability

CL_REL : 226 : clearance (L/day) = 9.4 L/h x 24

V_REL : 3700 : Vd (L)

//--- Elagolix PK (150 or 200 mg PO; F~50%; Vd~1900 L; CL~125 L/h) Winzenborg 2018

KA_ELA : 2.5 : 1/day

F_ELA : 0.50

CL_ELA : 3000 : L/day

V_ELA : 1900 : L

//--- Leuprolide depot 3.75 mg IM q28d (zero-order release ~ 0.13 mg/d) Periti 2002

F_LEU : 0.94

KREL_LEU : 0.025 : 1/day (depot release)

CL_LEU : 200 : L/day

V_LEU : 27 : L

//--- Dienogest 2 mg PO QD Foster 2008 (F~91%, Vd~40 L, CL~5.4 L/h ≈ 130 L/d)

KA_DNG : 5.0

F_DNG : 0.91

CL_DNG : 130

V_DNG : 40

//--- LNG-IUS 52 mg (intrauterine reservoir, ~20 µg/d local + spillover) Sheng 2009

KREL_LNG : 0.000028 : 1/day (slow reservoir release fraction; 52 mg reservoir × 0.000028 ≈ 0.02 mg/d ~ 20 µg/d)

F_SYS_LNG : 0.10 : fraction spilling to systemic

CL_LNG : 65 : L/day (LNG plasma CL)

V_LNG : 100 : L

//--- Letrozole 2.5 mg PO QD Sioufi 1997 (F~99.9%; Vd~1.9 L/kg; CL~2.1 L/h = 50 L/d)

KA_LET : 5.0

F_LET : 0.99

CL_LET : 50

V_LET : 120

//--- Ibuprofen 400 mg q6h Davies 1998 (F~0.95; Vd~10 L; CL~3 L/h = 72 L/d)

KA_IBU : 12

F_IBU : 0.95

CL_IBU : 72

V_IBU : 10

//--- Tranexamic acid 1 g PO q6h × 5 d (F=0.45; Vd 0.21 L/kg; CL ~6 L/h = 144 L/d)

KA_TXA : 6

F_TXA : 0.45

CL_TXA : 144

V_TXA : 14

//--- HPO axis (Pampaloni-type physiologic surrogate, daily mean)

GnRH_BASE : 1.0 : relative GnRH pulse amplitude

FSH_BASE : 6.0 : IU/L

LH_BASE : 7.0 : IU/L

E2_BASE : 110 : pg/mL (mid-follicular average)

P4_BASE : 5.0 : ng/mL (luteal phase average)

KIN_FSH : 6.0

KOUT_FSH : 1.0

KIN_LH : 7.0

KOUT_LH : 1.0

KIN_E2 : 110

KOUT_E2 : 1.0

KIN_P4 : 5.0

KOUT_P4 : 1.0

//--- Drug effects on GnRHR

IC50_REL : 0.005 : mg/L on GnRH signaling

IC50_ELA : 0.10 : mg/L (200 mg dose drives lower E2 than 150)

KAGON_LEU : 0.20 : initial flare (multiplier per mg/L Lupron)

KDESENS : 0.08 : 1/day desensitization rate post-flare

//--- Local-lesion biology (PGE2-aromatase positive feedback)

KIN_AROM : 1.0 : baseline lesion aromatase synthesis (relative units)

KOUT_AROM : 0.10 : 1/day

EMAX_PGE : 3.0 : PGE2 fold-induction of aromatase

EC50_PGE : 1.5 : (PGE2 units)

KIN_PGE : 1.0

KOUT_PGE : 0.50

EMAX_COX : 4.0

EC50_COX : 0.5

//--- Local E2 (intra-lesional) — proportional to systemic E2 + aromatase

LE2_K_SYS : 0.6

LE2_K_LOC : 1.4

//--- TGF-β / fibrosis (cluster 7)

KIN_TGFB : 1.0

KOUT_TGFB : 0.10

EMAX_TGF_LE2 : 2.5

EC50_TGF_LE2 : 80 : intralesional E2 (pg/mL)

KFIB_FORM : 0.020

KFIB_DEG : 0.005

//--- Neuroangiogenesis (VEGF, NGF) and pain

KIN_VEGF : 1.0

KOUT_VEGF : 0.5

KVEGF_HIF : 1.5 : COX-2 / hypoxia drive

KIN_NGF : 1.0

KOUT_NGF : 0.5

NGF_FROM_COX : 0.6

NGF_FROM_VEGF: 0.4

//--- JZ thickness dynamics (mm)

KOUT_JZ : 0.010 : 1/day

KIN_JZ : 0.12 : units * mm /day

SCALE_JZ_E2: 0.060 : impact of local E2 (per pg/mL)

SCALE_JZ_FB: 4.0 : fibrosis weight

EFF_FIBRO_LNG : 0.3 : LNG-IUS direct atrophy of basalis

//--- Heavy menstrual bleeding (PBAC)

KOUT_PBAC : 0.07

SCALE_PBAC_JZ : 12 : units per mm JZ

SCALE_PBAC_VEGF : 30 : units per VEGF

SCALE_PBAC_LNG : 0.60 : direct LNG endometrial atrophy

SCALE_PBAC_TXA : 0.45 : TXA hemostatic ceiling (fractional reduction)

//--- Dysmenorrhea VAS

KOUT_VAS : 0.06

SCALE_VAS_PGE : 1.6

SCALE_VAS_NGF : 1.4

SCALE_VAS_JZ : 0.05

SCALE_VAS_NSAID : 0.5

//--- QoL EHP-30 (lower=better; baseline 60)

KOUT_QOL : 0.05

SCALE_QOL_VAS : 4.0

SCALE_QOL_PBAC : 0.08

//--- Hemoglobin (g/dL) coupled to PBAC

KOUT_HB : 0.020

HB_TARGET : 13.5 : healthy adult female

HB_LOSS_K : 0.006 : g/dL per PBAC unit per cycle

//--- BMD (g/cm^2) coupled to systemic estradiol

KOUT_BMD : 0.0018

EC50_BMD_E2 : 35

EMAX_BMD_LOSS : 0.0015

//--- Add-back (E2 1 mg + NETA 0.5 mg) binary flag from infusion

ADDBACK_ON : 0

ADDBACK_E2_BOOST : 30 : pg/mL systemic baseline restore

ADDBACK_BMD_BOOST: 0.25 : fraction protection vs no add-back

//--- Letrozole effect on aromatase (Ki ~12 nM ≈ 0.003 mg/L)

KI_LET : 0.003

//--- Mifepristone / ulipristal antagonism on PR (binary flag)

SPRM_ON : 0

SPRM_DEEP_FX : 0.4

//--- Surgery toggles (binary; applied as multiplicative collapse)

HYS_ON : 0

UAE_ON : 0

HIFU_ON : 0

ABLAT_ON : 0

[CMT] @annotated

GUT_REL : Relugolix gut depot (mg)

CEN_REL : Relugolix central (mg)

GUT_ELA : Elagolix gut depot (mg)

CEN_ELA : Elagolix central (mg)

DEP_LEU : Leuprolide IM depot (mg)

CEN_LEU : Leuprolide central (mg)

GUT_DNG : Dienogest gut (mg)

CEN_DNG : Dienogest central (mg)

RES_LNG : LNG-IUS reservoir (mg)

CEN_LNG : LNG systemic (mg)

GUT_LET : Letrozole gut (mg)

CEN_LET : Letrozole central (mg)

GUT_IBU : Ibuprofen gut (mg)

CEN_IBU : Ibuprofen central (mg)

GUT_TXA : TXA gut (mg)

CEN_TXA : TXA central (mg)

FSH : pituitary FSH (IU/L)

LH : pituitary LH (IU/L)

E2 : systemic estradiol (pg/mL)

P4 : systemic progesterone (ng/mL)

AROM : lesion aromatase activity (a.u.)

PGE : lesion COX-2/PGE2 axis (a.u.)

LE2 : intralesional E2 (pg/mL)

TGFB : TGF-β tone (a.u.)

FIBROSIS : periglandular fibrosis index (0-3)

VEGF : VEGF (a.u.)

NGF : NGF (a.u.)

JZ : junctional-zone thickness (mm)

PBAC : heavy menstrual bleeding score

VAS : dysmenorrhea VAS 0-10

EHP30 : EHP-30 QoL (lower better)

HB : hemoglobin (g/dL)

BMD : lumbar BMD (g/cm^2)

[MAIN]

// Initial conditions

GUT_REL_0 = 0; CEN_REL_0 = 0;

GUT_ELA_0 = 0; CEN_ELA_0 = 0;

DEP_LEU_0 = 0; CEN_LEU_0 = 0;

GUT_DNG_0 = 0; CEN_DNG_0 = 0;

RES_LNG_0 = 0; CEN_LNG_0 = 0;

GUT_LET_0 = 0; CEN_LET_0 = 0;

GUT_IBU_0 = 0; CEN_IBU_0 = 0;

GUT_TXA_0 = 0; CEN_TXA_0 = 0;

FSH_0 = FSH_BASE;

LH_0 = LH_BASE;

E2_0 = E2_BASE;

P4_0 = P4_BASE;

AROM_0 = 1 + 0.5*(ADENO_SEV-1); // lesion has elevated aromatase

PGE_0 = 1 + 0.5*(ADENO_SEV-1);

LE2_0 = E2_BASE * 1.4 + 40*(ADENO_SEV-1);

TGFB_0 = 1 + 0.5*(ADENO_SEV-1);

FIBROSIS_0 = 0.3*ADENO_SEV;

VEGF_0 = 1 + 0.3*(ADENO_SEV-1);

NGF_0 = 1 + 0.3*(ADENO_SEV-1);

JZ_0 = BASE_JZ;

PBAC_0 = BASE_PBAC;

VAS_0 = BASE_VAS;

EHP30_0 = 35 + 8*ADENO_SEV;

HB_0 = BASE_HB;

BMD_0 = BASE_BMD;

[ODE]

// ---------- PK ----------

double CREL = CEN_REL / V_REL;

double CELA = CEN_ELA / V_ELA;

double CLEU = CEN_LEU / V_LEU;

double CDNG = CEN_DNG / V_DNG;

double CLNG = CEN_LNG / V_LNG;

double CLET = CEN_LET / V_LET;

double CIBU = CEN_IBU / V_IBU;

double CTXA = CEN_TXA / V_TXA;

dxdt_GUT_REL = -KA_REL * GUT_REL;

dxdt_CEN_REL = KA_REL * GUT_REL - (CL_REL/V_REL) * CEN_REL;

dxdt_GUT_ELA = -KA_ELA * GUT_ELA;

dxdt_CEN_ELA = KA_ELA * GUT_ELA - (CL_ELA/V_ELA) * CEN_ELA;

dxdt_DEP_LEU = -KREL_LEU * DEP_LEU;

dxdt_CEN_LEU = KREL_LEU * DEP_LEU - (CL_LEU/V_LEU) * CEN_LEU;

dxdt_GUT_DNG = -KA_DNG * GUT_DNG;

dxdt_CEN_DNG = KA_DNG * GUT_DNG - (CL_DNG/V_DNG) * CEN_DNG;

dxdt_RES_LNG = -KREL_LNG * RES_LNG;

dxdt_CEN_LNG = F_SYS_LNG * KREL_LNG * RES_LNG - (CL_LNG/V_LNG) * CEN_LNG;

dxdt_GUT_LET = -KA_LET * GUT_LET;

dxdt_CEN_LET = KA_LET * GUT_LET - (CL_LET/V_LET) * CEN_LET;

dxdt_GUT_IBU = -KA_IBU * GUT_IBU;

dxdt_CEN_IBU = KA_IBU * GUT_IBU - (CL_IBU/V_IBU) * CEN_IBU;

dxdt_GUT_TXA = -KA_TXA * GUT_TXA;

dxdt_CEN_TXA = KA_TXA * GUT_TXA - (CL_TXA/V_TXA) * CEN_TXA;

// ---------- HPO ----------

// GnRH antagonists (REL, ELA) competitively reduce GnRH→GnRHR signal

// Leuprolide initially flares (agonist), then desensitizes; modeled as

// a smooth bi-phasic effect via cumulative exposure (CEN_LEU acts on both).

double SUP_REL = CREL / (IC50_REL + CREL);

double SUP_ELA = CELA / (IC50_ELA + CELA);

double LEU_FLARE = (CLEU>0)? KAGON_LEU * CLEU * exp(-KDESENS * SOLVERTIME) : 0;

double LEU_SUP = (CLEU>0)? (1 - exp(-KDESENS * SOLVERTIME)) : 0;

double GNRH_DRIVE = GnRH_BASE * (1 - SUP_REL) * (1 - SUP_ELA) * (1 - 0.95*LEU_SUP)

+ LEU_FLARE;

// Letrozole/anastrozole inhibit aromatase → reduce ovarian E2 production

double AROM_OVARY_INH = 1 / (1 + CLET / KI_LET);

// Dienogest/MPA/LNG suppress ovulation: scale FSH/LH amplitude

double PROG_SUPP = 1 / (1 + CDNG*0.5 + CLNG*5.0);

// Add-back boost

double EADD = (ADDBACK_ON>0) ? ADDBACK_E2_BOOST : 0;

dxdt_FSH = KIN_FSH * GNRH_DRIVE * PROG_SUPP - KOUT_FSH * FSH;

dxdt_LH = KIN_LH * GNRH_DRIVE * PROG_SUPP - KOUT_LH * LH;

// Ovarian E2 driven by LH/FSH and aromatase inhibition

dxdt_E2 = KIN_E2 * (FSH/FSH_BASE) * AROM_OVARY_INH + EADD*KOUT_E2

- KOUT_E2 * E2;

// Progesterone driven by LH (luteal) and suppressed by ovulation-blocking drugs

double PROG_BLOCK = 0;

if (CDNG > 0) PROG_BLOCK += CDNG / (CDNG + 0.2);

if (CLNG > 0) PROG_BLOCK += CLNG / (CLNG + 0.001);

if (PROG_BLOCK > 0.95) PROG_BLOCK = 0.95;

dxdt_P4 = KIN_P4 * (LH/LH_BASE) * (1 - PROG_BLOCK) - KOUT_P4 * P4

+ (CDNG>0 ? 1.0*CDNG : 0) // dienogest itself counts as PR-agonist signal (surrogate)

+ (CLNG>0 ? 5.0*CLNG : 0);

// ---------- Local lesion biology ----------

// COX-2 / PGE2 driven by inflammation; inhibited by NSAID via ibuprofen

double COX_INH_NSAID = 1 / (1 + CIBU/0.05);

dxdt_PGE = KIN_PGE * (1 + 0.4*FIBROSIS) * COX_INH_NSAID - KOUT_PGE * PGE;

// Aromatase: PGE2 induces (Bulun mechanism); letrozole/anastrozole inhibit local

double AROM_LOCAL_INH = 1 / (1 + CLET / KI_LET);

dxdt_AROM = KIN_AROM * (1 + EMAX_PGE * PGE/(EC50_PGE + PGE)) * AROM_LOCAL_INH

- KOUT_AROM * AROM;

// Intralesional E2: function of systemic E2 and local aromatase

dxdt_LE2 = (LE2_K_SYS * E2 + LE2_K_LOC * AROM * 80) * 0.05 - 0.05 * LE2;

// TGF-β driven by local E2 and PGE2; SPRM partially blocks

double SPRM_FACTOR = (SPRM_ON>0) ? (1 - SPRM_DEEP_FX) : 1.0;

dxdt_TGFB = KIN_TGFB * (1 + EMAX_TGF_LE2 * LE2/(EC50_TGF_LE2 + LE2))

* SPRM_FACTOR - KOUT_TGFB * TGFB;

// Fibrosis accumulates from TGFB and reverses slowly

dxdt_FIBROSIS = KFIB_FORM * TGFB - KFIB_DEG * FIBROSIS;

if (HYS_ON>0) dxdt_FIBROSIS = -1.0 * FIBROSIS; // hysterectomy

if (HIFU_ON>0) dxdt_FIBROSIS += -0.3 * FIBROSIS; // partial ablation

// VEGF/NGF

dxdt_VEGF = KIN_VEGF * (1 + KVEGF_HIF * PGE) - KOUT_VEGF * VEGF;

dxdt_NGF = KIN_NGF * (NGF_FROM_COX * PGE + NGF_FROM_VEGF * VEGF) - KOUT_NGF * NGF;

// ---------- Junctional-zone thickness ----------

double JZ_DRIVE = SCALE_JZ_E2 * (LE2 - 80) + SCALE_JZ_FB * (FIBROSIS - 0.3);

if (JZ_DRIVE < -10) JZ_DRIVE = -10;

double LNG_ATR = (CLNG>0) ? EFF_FIBRO_LNG : 0;

dxdt_JZ = KIN_JZ * (JZ_DRIVE/8) - KOUT_JZ * (JZ - 6) - LNG_ATR;

if (HYS_ON>0) dxdt_JZ = -2 * JZ;

if (UAE_ON>0) dxdt_JZ -= 0.02 * JZ;

if (HIFU_ON>0) dxdt_JZ -= 0.03 * JZ;

// ---------- HMB / PBAC ----------

double PBAC_TARGET = 30 + SCALE_PBAC_JZ * (JZ - 6) + SCALE_PBAC_VEGF * (VEGF - 1);

if (PBAC_TARGET < 20) PBAC_TARGET = 20;

double LNG_PBAC_FX = (CLNG>0) ? (1 - SCALE_PBAC_LNG) : 1;

double TXA_PBAC_FX = 1 - SCALE_PBAC_TXA * (CTXA/(CTXA + 5));

if (ABLAT_ON>0) PBAC_TARGET *= 0.25;

if (HYS_ON>0) PBAC_TARGET = 0;

dxdt_PBAC = KOUT_PBAC * (PBAC_TARGET * LNG_PBAC_FX * TXA_PBAC_FX - PBAC);

// ---------- VAS dysmenorrhea ----------

double VAS_TARGET = 0.5

+ SCALE_VAS_PGE * (PGE - 1)

+ SCALE_VAS_NGF * (NGF - 1)

+ SCALE_VAS_JZ * (JZ - 6);

if (CIBU>0) VAS_TARGET *= (1 - SCALE_VAS_NSAID);

if (VAS_TARGET < 0) VAS_TARGET = 0;

if (VAS_TARGET > 10) VAS_TARGET = 10;

dxdt_VAS = KOUT_VAS * (VAS_TARGET - VAS);

// ---------- QoL ----------

double EHP_TARGET = 5 + SCALE_QOL_VAS * VAS + SCALE_QOL_PBAC * PBAC;

if (EHP_TARGET > 100) EHP_TARGET = 100;

dxdt_EHP30 = KOUT_QOL * (EHP_TARGET - EHP30);

// ---------- Hemoglobin ----------

double HB_DRIVE = HB_TARGET - HB_LOSS_K * (PBAC - 30);

if (HB_DRIVE < 6) HB_DRIVE = 6;

if (HB_DRIVE > 15) HB_DRIVE = 15;

dxdt_HB = KOUT_HB * (HB_DRIVE - HB);

// ---------- BMD ----------

// systemic estradiol drives BMD; hypoestrogenic states cause loss;

// add-back partially restores

double BMD_LOSS = EMAX_BMD_LOSS * (1 - E2/(E2 + EC50_BMD_E2));

if (ADDBACK_ON>0) BMD_LOSS *= (1 - ADDBACK_BMD_BOOST);

dxdt_BMD = -BMD_LOSS + KOUT_BMD * (1.05 - BMD);

[TABLE]

capture conc_relugolix = CEN_REL / V_REL;

capture conc_elagolix = CEN_ELA / V_ELA;

capture conc_leuprolide = CEN_LEU / V_LEU;

capture conc_dienogest = CEN_DNG / V_DNG;

capture conc_LNG = CEN_LNG / V_LNG;

capture conc_letrozole = CEN_LET / V_LET;

capture conc_ibuprofen = CEN_IBU / V_IBU;

capture conc_TXA = CEN_TXA / V_TXA;

capture FSH_IUL = FSH;

capture LH_IUL = LH;

capture E2_pgmL = E2;

capture LocalE2_pgmL = LE2;

capture P4_ngmL = P4;

capture COX2_PGE2 = PGE;

capture Aromatase = AROM;

capture TGFb = TGFB;

capture Fibrosis_score = FIBROSIS;

capture VEGF_score = VEGF;

capture NGF_score = NGF;

capture JZ_mm = JZ;

capture PBAC_score = PBAC;

capture VAS_pain = VAS;

capture EHP30_QoL = EHP30;

capture Hb_gdL = HB;

capture BMD_gcm2 = BMD;

[CAPTURE]

conc_relugolix conc_elagolix conc_leuprolide conc_dienogest conc_LNG

conc_letrozole conc_ibuprofen conc_TXA

FSH_IUL LH_IUL E2_pgmL LocalE2_pgmL P4_ngmL

COX2_PGE2 Aromatase TGFb Fibrosis_score VEGF_score NGF_score

JZ_mm PBAC_score VAS_pain EHP30_QoL Hb_gdL BMD_gcm2

## ============================================================================

## R-side scenario helpers (parsed by users, not by mrgsolve)

## ============================================================================

## library(mrgsolve); library(dplyr); library(tidyr); library(ggplot2)

## mod <- mread_cache("adeno_mrgsolve_model.R")

## # ---------- 10 prebuilt scenarios ----------

## ADENO_simulate_scenarios <- function(end_d = 365) {

## sc <- list(

## "1. Untreated natural history" =

## ev(amt=0, cmt="CEN_REL", time=0),

## "2. NSAID + TXA symptomatic" =

## c(ev(amt=400, cmt="GUT_IBU", ii=0.25, addl=4*end_d),

## # TXA only during menses (5 days per 28-d cycle): pulse approximation

## ev(amt=1000, cmt="GUT_TXA", time=seq(0, end_d, 28), ii=0.25, addl=4*5)),

## "3. Continuous COC" =

## ev(amt=0, cmt="CEN_DNG", time=0), # surrogate via PROG_SUPP path - off-model placeholder

## "4. Dienogest 2 mg PO QD" =

## ev(amt=2, cmt="GUT_DNG", ii=1, addl=end_d),

## "5. LNG-IUS 52 mg (5-yr reservoir)" =

## ev(amt=52, cmt="RES_LNG", time=0),

## "6. Leuprolide depot 3.75 mg q4w (no add-back)" =

## ev(amt=3.75, cmt="DEP_LEU", ii=28, addl=ceiling(end_d/28)),

## "7. Leuprolide + add-back (E2 1 mg / NETA 0.5 mg)" =

## ev(amt=3.75, cmt="DEP_LEU", ii=28, addl=ceiling(end_d/28)) %>%

## mutate(ADDBACK_ON = 1),

## "8. Relugolix-CT 40 mg PO QD" =

## ev(amt=40, cmt="GUT_REL", ii=1, addl=end_d) %>%

## mutate(ADDBACK_ON = 1),

## "9. Elagolix 200 mg PO BID" =

## ev(amt=200, cmt="GUT_ELA", ii=0.5, addl=2*end_d) %>%

## mutate(ADDBACK_ON = 0),

## "10. Letrozole 2.5 mg PO QD" =

## ev(amt=2.5, cmt="GUT_LET", ii=1, addl=end_d)

## )

## purrr::imap_dfr(sc, function(e, lab) {

## mod %>% mrgsim(e, end=end_d, delta=1) %>%

## as_tibble() %>% mutate(scenario=lab)

## })

## }

## # ---------- Calibration anchors ----------

## # Relugolix-CT (SPIRIT) : VAS BPI reduction at 24 wk ≥ 30% → match VAS_pain

## # Elagolix EM-I/II : DYS responder ≥50% at 6 mo (200 mg) → match VAS

## # Dienogest KIM-ADENO : VAS 6.5 → 1.6 over 24 wk; JZ 11→8 mm at 24 wk

## # LNG-IUS (Sheng 2009) : PBAC 270→55 at 6 mo, Hb +1.8 g/dL at 12 mo,

## # uterine volume ↓ 25–35 % at 12 mo

## # Leuprolide depot : E2 → <20 pg/mL by week 4 (post-flare); BMD −3.5%/6mo

## # Add-back (Pierce 1999) : BMD loss attenuated 60–80%

## # Letrozole (Kim 2013) : VAS 8→2.5, uterine volume −60 mL @ 12 wk

## # ---------- Quick sanity plots ----------

## # df <- ADENO_simulate_scenarios(365)

## # ggplot(df, aes(time, VAS_pain, colour=scenario)) + geom_line()

## # ggplot(df, aes(time, PBAC_score, colour=scenario)) + geom_line()

## # ggplot(df, aes(time, JZ_mm, colour=scenario)) + geom_line()

## # ggplot(df, aes(time, E2_pgmL, colour=scenario)) + geom_line()

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