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Dupilumab exposure and atopic-dermatitis response

A coupled subcutaneous PK and indirect-response model linking dupilumab exposure to EASI and IGA response dynamics while accounting for patient and disease covariates.

Integrated Exposure–Response of Dupilumab in Children, Adolescents, and Adults With Atopic Dermatitis Using Categorical and Continuous Efficacy Assessments: A Population Analysis ↗

Pharmaceutical Research

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MODEL IN MOTION 18 sec

How do the adult and child presets connect drug amount with skin response?

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Adult severe AD 600 mg load, 300 mg every 2 weeks

How do dupilumab exposure and patient covariates shape the onset and depth of EASI and IGA response?

0–112 day

Scenario details

Adult severe AD 600 mg load, 300 mg every 2 weeks

How do dupilumab exposure and patient covariates shape the onset and depth of EASI and IGA response?

Readouts

Central dupilumab concentration · Unit unavailable
Central dupilumab concentration over the selected simulation window.
EASI response · dimensionless
EASI response over the selected simulation window.
IGA response · dimensionless
IGA response over the selected simulation window.
Exposure (AUC) · mg*day/L
Exposure (AUC) over the selected simulation window.

Study purpose

  • How do dupilumab exposure and patient covariates shape the onset and depth of EASI and IGA response?

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Model parameter

Body weight used for body-size scaling in the model.

kg

Suggested: 38.1–114. You can explore beyond this range.

76.1 → —

EASI IC50 at which the corresponding modeled process is inhibited by half.

mg/L

Suggested: 10.2–30.5. You can explore beyond this range.

20.3 → —

EASI Imax defining the limiting magnitude of the corresponding pharmacodynamic effect.

—

Suggested: 0.133–0.399. You can explore beyond this range.

0.266 → —

EASI effect half-life controlling the time required for the corresponding quantity to decrease by half.

day

Suggested: 6.85–20.5. You can explore beyond this range.

13.7 → —

IGA IC50 at which the corresponding modeled process is inhibited by half.

mg/L

Suggested: 13.6–40.7. You can explore beyond this range.

27.1 → —
Simulation time
day
day
112 → 168

Time between reported samples.

day
7 → 1

2 changes · Variation 1

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Biology

A subcutaneous dupilumab dose passes through a depot and three transit stages, reaches central exposure, exchanges with a peripheral pool, undergoes linear and saturable elimination, and modulates empirical EASI and IGA response turnover.

How does subcutaneous dupilumab exposure drive delayed EASI and IGA responses?A subcutaneous dupilumab dose passes through a depot and three transit stages, reaches central exposure, exchanges with a peripheral pool, undergoes linear and saturable elimination, and modulates empirical EASI and IGA response turnover.BIOLOGY OVERVIEWHow does subcutaneous dupilumab exposure drive delayed EASI and IGA responses?Subcutaneous dose: Dupilumab administrationSubcutaneous doseDupilumab administrationDepot + transit chain: Three staged absorption delaysDepot + transitchainThree staged absorption delaysCentral exposure: Dupilumab concentrationCentral exposureDupilumab concentrationPeripheral pool: Reversible distributionPeripheral poolReversible distributionPK elimination: Linear and saturable lossPK eliminationLinear and saturable lossEASI + IGA turnover: Empirical exposure-linked responsesEASI + IGAturnoverEmpirical exposure-linkedresponsesCumulative exposure: Central concentration integralCumulativeexposureCentral concentration integralPRIMARY READOUTSCentral dupilumab concentrationCentral dupilumab concentr…EASI responseEASI responseIGA responseIGA responseCumulative exposureCumulative exposure

Solid arrows show modeled movement or change; two-headed arrows show reversible exchange; dashed arrows show modulation without material transfer.

Model scope: IL-4R binding, receptor occupancy, cytokine signaling, and lesion biology are not explicit; the pharmacodynamics are empirical exposure-linked response turnover.

Modeled relationships (6)
  • Subcutaneous dose → Depot + transit chain: SC input (flow)
  • Depot + transit chain → Central exposure: transit (flow)
  • Central exposure ↔ Peripheral pool: distribution (reversible exchange)
  • Central exposure → PK elimination: linear + saturable (loss)
  • Central exposure → EASI + IGA turnover: exposure effect (modulation)
  • Central exposure → Cumulative exposure: integrates C (production)

Modeled relationships: Subcutaneous dose to Depot + transit chain: SC input (flow); Depot + transit chain to Central exposure: transit (flow); Central exposure reversibly exchanges with Peripheral pool: distribution (reversible exchange); Central exposure to PK elimination: linear + saturable (loss); Central exposure to EASI + IGA turnover: exposure effect (modulation); Central exposure to Cumulative exposure: integrates C (production).

Primary readouts: Central dupilumab concentration; EASI response; IGA response; Cumulative exposure.

Model details

53 parameters · 10 states · 10 equations · 12 derived outputs

Classification & API access
Therapeutic
Dupilumab
Modality
Monoclonal antibody
Target
IL4R, CD124
Disease / scope
Moderate-to-severe atopic dermatitis
ParameterDefaultUnitDescription
Ada positiveada_positive0—Ada positive coefficient used by the released system of model equations.
Age decadeage_decade_year10yearAge decade coefficient used by the released system of model equations.
Ageage_year37.7yearAge coefficient used by the released system of model equations.
Serum albuminalbumin_g_l44g/LSerum albumin used by this model.
Asian raceasian_race0—Asian race coefficient used by the released system of model equations.
Baseline EASI scorebaseline_easi_score30.4—Baseline EASI score coefficient used by the released system of model equations.
Baseline eos 10e9baseline_eos_10e9_l0.481Gcell/LBaseline eos 10e9 coefficient used by the released system of model equations.
Baseline tarcbaseline_tarc_pg_ml2033.6pg/mLBaseline tarc coefficient used by the released system of model equations.
Bmibmi_kg_m226.1kg/(meter²)Bmi coefficient used by the released system of model equations.
Body weightbody_weight_kg76.1kgBody weight used for body-size scaling in the model.
EASI age baselineeasi_age_baseline-0.0372—EASI age baseline coefficient used by the released system of model equations.
EASI asian drugeasi_asian_drug-0.374—EASI asian drug coefficient used by the released system of model equations.
EASI effect half-lifeeasi_effect_half_life_day13.7dayEASI effect half-life controlling the time required for the corresponding quantity to decrease by half.
EASI ET50easi_et50_day29.2dayEASI ET50 coefficient used by the released system of model equations.
EASI IC50easi_ic50_mg_l20.3mg/LEASI IC50 at which the corresponding modeled process is inhibited by half.
EASI Imaxeasi_imax0.266—EASI Imax defining the limiting magnitude of the corresponding pharmacodynamic effect.
EASI lambdaeasi_lambda0.4—EASI lambda coefficient used by the released system of model equations.
EASI log eos baselineeasi_log_eos_baseline0.0173—EASI log eos baseline coefficient used by the released system of model equations.
EASI log eos drugeasi_log_eos_drug-0.057—EASI log eos drug coefficient used by the released system of model equations.
EASI log tarc baselineeasi_log_tarc_baseline0.0508—EASI log tarc baseline coefficient used by the released system of model equations.
EASI pmaxeasi_pmax-1.24—EASI pmax coefficient used by the released system of model equations.
EASI prior baselineeasi_prior_baseline0.0233—EASI prior baseline coefficient used by the released system of model equations.
EASI prior pmaxeasi_prior_pmax-0.166—EASI prior pmax coefficient used by the released system of model equations.
EASI tcs baselineeasi_tcs_baseline-0.0218—EASI tcs baseline coefficient used by the released system of model equations.
EASI tcs pmaxeasi_tcs_pmax0.232—EASI tcs pmax coefficient used by the released system of model equations.
EASI weight drugeasi_weight_drug-0.185—EASI weight drug coefficient used by the released system of model equations.
F subcutaneousf_sc0.642—F subcutaneous coefficient used by the released system of model equations.
IGA effect half-lifeiga_effect_half_life_day19.7dayIGA effect half-life controlling the time required for the corresponding quantity to decrease by half.
IGA IC50iga_ic50_mg_l27.1mg/LIGA IC50 at which the corresponding modeled process is inhibited by half.
K23k23_day0.2111/dayK23 coefficient used by the released system of model equations.
K32k32_day0.311/dayK32 coefficient used by the released system of model equations.
Absorption rate constantka_day0.3061/dayAbsorption rate constant governing entry from the administration site.
Ke ada effectke_ada_effect0.164—Ke ada effect coefficient used by the released system of model equations.
Ke bmi powerke_bmi_power0.368—Ke bmi power coefficient used by the released system of model equations.
Keke_day0.04771/dayKe coefficient used by the released system of model equations.
Ke EASI powerke_easi_power0.143—Ke EASI power coefficient used by the released system of model equations.
Ke white effectke_white_effect-0.123—Ke white effect coefficient used by the released system of model equations.
Kmkm_mg_l0.01mg/LKm coefficient used by the released system of model equations.
Mttmtt_day0.105dayMtt coefficient used by the released system of model equations.
Prior immunotherapy flagprior_immunotherapy_flag0—Prior immunotherapy flag coefficient used by the released system of model equations.
Reference agereference_age_year37.7yearReference age coefficient used by the released system of model equations.
Reference serum albuminreference_albumin_g_l44g/LReference serum albumin used by this model.
Reference bmireference_bmi_kg_m226.1kg/(meter²)Reference bmi coefficient used by the released system of model equations.
Reference body weightreference_body_weight_kg76.1kgReference body weight used for body-size scaling in the model.
Reference EASI scorereference_easi_score30.4—Reference EASI score coefficient used by the released system of model equations.
Reference eos 10e9reference_eos_10e9_l0.481Gcell/LReference eos 10e9 coefficient used by the released system of model equations.
Reference tarcreference_tarc_pg_ml2033.6pg/mLReference tarc coefficient used by the released system of model equations.
Tcs flagtcs_flag0—Tcs flag coefficient used by the released system of model equations.
Distribution volume 2 albumin powerv2_albumin_power-0.653—Distribution volume 2 albumin power used to convert modeled amount to concentration in the relevant compartment.
Peripheral distribution volumev2_l2.74LPeripheral distribution volume used to convert modeled amount to concentration in the relevant compartment.
Distribution volume 2 weight powerv2_weight_power0.817—Distribution volume 2 weight power used to convert modeled amount to concentration in the relevant compartment.
Vmvm_mg_l_day1.07mg/L/dayVm coefficient used by the released system of model equations.
White racewhite_race0—White race coefficient used by the released system of model equations.

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