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Isatuximab, M-protein and FcRn competition PBPK

Explore fixed-effect isatuximab disposition and M-protein competition for FcRn salvage across 15 organs, with an optional IVIG competition scenario. Independently inferred initialization and omitted constants are explicit assumptions; population uncertainty is not represented.

Mechanistic modeling of time-dependent antibody clearance in multiple myeloma: A physiologically based pharmacokinetic model of isatuximab ↗

Journal of Pharmaceutical Sciences

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Average response under isatuximab

Fixed-effect equation implementation with inferred omitted constants and initialization. Not a population prediction or individual dose recommendation. An 85 kg representative patient receives 10 mg/kg IV isatuximab at weeks 0–4 and every two weeks thereafter while the responsive component of M-protein synthesis declines.

0–4,704 hour

Scenario details

Average response under isatuximab

Fixed-effect equation implementation with inferred omitted constants and initialization. Not a population prediction or individual dose recommendation. An 85 kg representative patient receives 10 mg/kg IV isatuximab at weeks 0–4 and every two weeks thereafter while the responsive component of M-protein synthesis declines.

Readouts

Circulating m protein · g/L
mprotein g L
Plasma isatuximab · nM
isatuximab nM
Model derived isatuximab clearance · L/h
total clearance l h

Study purpose

  • How does falling M-protein reduce FcRn competition and change isatuximab exposure and clearance?

Assumptions

  • This is a source-limited mechanistic reconstruction, not an exact replay of the unavailable native systems-modeling environment project.
  • The 85 kg representative weight and steady-state initialization are reconstruction assumptions.
  • Aggregate digitized curves are not patient-level records or a dosing recommendation.

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Simulation time
h
h
4704 → 168

Time between reported samples.

h
24 → 1

2 changes · Variation 1

Biology

Explore fixed-effect isatuximab disposition and M-protein competition for FcRn salvage across 15 organs, with an optional IVIG competition scenario. Independently inferred initialization and omitted constants are explicit assumptions; population uncertainty is not represented.

Explore fixed-effect isatuximab disposition and M-protein competition for FcRn salvage across 15 organs, with an optional IVIG competition scenario. Independently inferred initialization and omitted constants are explicit assumptions; population uncertainty is not represented.

Model details

105 parameters · 201 states · 201 equations · 7 derived outputs

Classification & API access
Therapeutic
isatuximab
Modality
Monoclonal antibody
Target
CD38, FcRn
Disease / scope
Multiple myeloma, monoclonal gammopathy
ParameterDefaultUnitDescription
Dose mg to plasma molardose_mg_to_plasma_molar2.1326508850501174e-9M/mgFixed input-unit conversion for 150 kDa IgG and 3.126 L plasma; not a biological fitted parameter.
Endosomal uptake ratep__CLup_per_h1.221/hPinocytic uptake rate shared by the modeled proteins across organ endosomes.
P frp__FR0.715—P fr coefficient used by the released system of model equations.
Endosomal fc rn poolp__FcRn_total_M0.0000943MShared endosomal FcRn binding-site concentration controlling salvage competition.
P gfrp__GFR_ml_h7200mL/hP gfr coefficient used by the released system of model equations.
P j lymphp__J_lymph_ml_h3670mL/hP j lymph coefficient used by the released system of model equations.
P mw mprot dap__MW_MPROT_Da150000—P mw mprot da coefficient used by the released system of model equations.
P mw en ig g dap__MW_enIgG_Da150000—P mw en ig g da coefficient used by the released system of model equations.
P mw ex ig g dap__MW_exIgG_Da150000—P mw ex ig g da coefficient used by the released system of model equations.
P v lymphp__V_lymph_ml274mLP v lymph coefficient used by the released system of model equations.
P v plasmap__V_plasma_ml3126mLP v plasma coefficient used by the released system of model equations.
P xjp__Xj0.38—P xj coefficient used by the released system of model equations.
P xp NM3p__Xp_nm313200—P xp NM3 coefficient used by the released system of model equations.
P adipose jp__adipose_J_ml_h22.466mL/hP adipose j coefficient used by the released system of model equations.
P adipose qp__adipose_Q_ml_h11233mL/hP adipose q governing exchange between model compartments.
P adipose vep__adipose_Ve_ml67.3mLP adipose ve coefficient used by the released system of model equations.
P adipose visp__adipose_Vis_ml2289mLP adipose vis coefficient used by the released system of model equations.
P adipose vvp__adipose_Vv_ml148mLP adipose vv coefficient used by the released system of model equations.
P alphap__alphaL0.042—P alpha coefficient used by the released system of model equations.
P alphap__alphaS0.958—P alpha coefficient used by the released system of model equations.
P bone jp__bone_J_ml_h5.182mL/hP bone j coefficient used by the released system of model equations.
P bone qp__bone_Q_ml_h2591mL/hP bone q governing exchange between model compartments.
P bone vep__bone_Ve_ml50.8mLP bone ve coefficient used by the released system of model equations.
P bone visp__bone_Vis_ml1891mLP bone vis coefficient used by the released system of model equations.
P bone vvp__bone_Vv_ml224mLP bone vv coefficient used by the released system of model equations.
P brain jp__brain_J_ml_h42.906mL/hP brain j coefficient used by the released system of model equations.
P brain qp__brain_Q_ml_h21453mL/hP brain q governing exchange between model compartments.
P brain vep__brain_Ve_ml7.25mLP brain ve coefficient used by the released system of model equations.
P brain visp__brain_Vis_ml261mLP brain vis coefficient used by the released system of model equations.
P brain vvp__brain_Vv_ml31.9mLP brain vv coefficient used by the released system of model equations.
P heart jp__heart_J_ml_h15.504mL/hP heart j coefficient used by the released system of model equations.
P heart qp__heart_Q_ml_h7752mL/hP heart q governing exchange between model compartments.
P heart vep__heart_Ve_ml1.71mLP heart ve coefficient used by the released system of model equations.
P heart visp__heart_Vis_ml48.8mLP heart vis coefficient used by the released system of model equations.
P heart vvp__heart_Vv_ml13.1mLP heart vv coefficient used by the released system of model equations.
Unbound endosomal degradationp__kdeg_per_h0.41/hFirst-order degradation of FcRn-unbound protein in organ endosomes.
P kidney jp__kidney_J_ml_h72.804mL/hP kidney j coefficient used by the released system of model equations.
P kidney qp__kidney_Q_ml_h36402mL/hP kidney q governing exchange between model compartments.
P kidney vep__kidney_Ve_ml1.66mLP kidney ve coefficient used by the released system of model equations.
P kidney visp__kidney_Vis_ml49.8mLP kidney vis coefficient used by the released system of model equations.
P kidney vvp__kidney_Vv_ml18.2mLP kidney vv coefficient used by the released system of model equations.
M protein dissociation from fc rnp__koff_MPROT38.31/hDissociation rate of the M-protein–FcRn complex in organ endosomes.
P dissociation rate en ig gp__koff_enIgG23.91/hP dissociation rate en ig g governing molecular dissociation in the binding model.
P dissociation rate ex ig gp__koff_exIgG23.91/hP dissociation rate ex ig g governing molecular dissociation in the binding model.
P association rate mprotp__kon_MPROT470000001/(M·h)P association rate mprot governing molecular association in the binding model.
P association rate en ig gp__kon_enIgG5600000001/(M·h)P association rate en ig g governing molecular association in the binding model.
P association rate ex ig gp__kon_exIgG5600000001/(M·h)P association rate ex ig g governing molecular association in the binding model.
P ksyn mprot infp__ksyn_MPROT_INF_M_h0.00000707M/hP ksyn mprot inf governing production or formation in the modeled biological process.
P ksyn mprot tp__ksyn_MPROT_T_M_h0.0000187M/hP ksyn mprot t governing production or formation in the modeled biological process.
P ksyn en ig gp__ksyn_enIgG_M_h4.7e-7M/hP ksyn en ig g governing production or formation in the modeled biological process.
M protein response ratep__ktv_per_h0.00114166666666666671/hRate constant for treatment-associated decline of the responsive M-protein synthesis component.
P large intestine jp__large_intestine_J_ml_h25.734mL/hP large intestine j coefficient used by the released system of model equations.
P large intestine qp__large_intestine_Q_ml_h12867mL/hP large intestine q governing exchange between model compartments.
P large intestine vep__large_intestine_Ve_ml2.74mLP large intestine ve coefficient used by the released system of model equations.
P large intestine visp__large_intestine_Vis_ml95.3mLP large intestine vis coefficient used by the released system of model equations.
P large intestine vvp__large_intestine_Vv_ml8.74mLP large intestine vv coefficient used by the released system of model equations.
P liver jp__liver_J_ml_h95.549mL/hP liver j coefficient used by the released system of model equations.
P liver qp__liver_Q_ml_h13210mL/hP liver q governing exchange between model compartments.
P liver vep__liver_Ve_ml10.7mLP liver ve coefficient used by the released system of model equations.
P liver visp__liver_Vis_ml429mLP liver vis coefficient used by the released system of model equations.
P liver vvp__liver_Vv_ml183mLP liver vv coefficient used by the released system of model equations.
P lung jp__lung_J_ml_h363.826mL/hP lung j coefficient used by the released system of model equations.
P lung qp__lung_Q_ml_h181913mL/hP lung q governing exchange between model compartments.
P lung vep__lung_Ve_ml5mLP lung ve coefficient used by the released system of model equations.
P lung visp__lung_Vis_ml300mLP lung vis coefficient used by the released system of model equations.
P lung vvp__lung_Vv_ml55mLP lung vv coefficient used by the released system of model equations.
P muscle jp__muscle_J_ml_h66.938mL/hP muscle j coefficient used by the released system of model equations.
P muscle qp__muscle_Q_ml_h33469mL/hP muscle q governing exchange between model compartments.
P muscle vep__muscle_Ve_ml150mLP muscle ve coefficient used by the released system of model equations.
P muscle visp__muscle_Vis_ml3910mLP muscle vis coefficient used by the released system of model equations.
P muscle vvp__muscle_Vv_ml662mLP muscle vv coefficient used by the released system of model equations.
P other jp__other_J_ml_h11.042mL/hP other j coefficient used by the released system of model equations.
P other qp__other_Q_ml_h5521mL/hP other q governing exchange between model compartments.
P other vep__other_Ve_ml24.3mLP other ve coefficient used by the released system of model equations.
P other visp__other_Vis_ml831mLP other vis coefficient used by the released system of model equations.
P other vvp__other_Vv_ml204mLP other vv coefficient used by the released system of model equations.
P pancreas jp__pancreas_J_ml_h6.112mL/hP pancreas j coefficient used by the released system of model equations.
P pancreas qp__pancreas_Q_ml_h3056mL/hP pancreas q governing exchange between model compartments.
P pancreas vep__pancreas_Ve_ml0.518mLP pancreas ve coefficient used by the released system of model equations.
P pancreas visp__pancreas_Vis_ml18mLP pancreas vis coefficient used by the released system of model equations.
P pancreas vvp__pancreas_Vv_ml5.7mLP pancreas vv coefficient used by the released system of model equations.
P rp__rL_nm22.9—P r coefficient used by the released system of model equations.
P rp__rS_nm4.44—P r coefficient used by the released system of model equations.
P sigma isp__sigma_IS0.2—P sigma is coefficient used by the released system of model equations.
P skin jp__skin_J_ml_h23.252mL/hP skin j coefficient used by the released system of model equations.
P skin qp__skin_Q_ml_h11626mL/hP skin q governing exchange between model compartments.
P skin vep__skin_Ve_ml17mLP skin ve coefficient used by the released system of model equations.
P skin visp__skin_Vis_ml1125mLP skin vis coefficient used by the released system of model equations.
P skin vvp__skin_Vv_ml127mLP skin vv coefficient used by the released system of model equations.
P small intestine jp__small_intestine_J_ml_h24.736mL/hP small intestine j coefficient used by the released system of model equations.
P small intestine qp__small_intestine_Q_ml_h12368mL/hP small intestine q governing exchange between model compartments.
P small intestine vep__small_intestine_Ve_ml1.93mLP small intestine ve coefficient used by the released system of model equations.
P small intestine visp__small_intestine_Vis_ml67.1mLP small intestine vis coefficient used by the released system of model equations.
P small intestine vvp__small_intestine_Vv_ml6.15mLP small intestine vv coefficient used by the released system of model equations.
P spleen jp__spleen_J_ml_h12.686mL/hP spleen j coefficient used by the released system of model equations.
P spleen qp__spleen_Q_ml_h6343mL/hP spleen q governing exchange between model compartments.
P spleen vep__spleen_Ve_ml1.11mLP spleen ve coefficient used by the released system of model equations.
P spleen visp__spleen_Vis_ml44.3mLP spleen vis coefficient used by the released system of model equations.
P spleen vvp__spleen_Vv_ml26.8mLP spleen vv coefficient used by the released system of model equations.
P thymus jp__thymus_J_ml_h0.706mL/hP thymus j coefficient used by the released system of model equations.
P thymus qp__thymus_Q_ml_h353mL/hP thymus q governing exchange between model compartments.
P thymus vep__thymus_Ve_ml0.0321mLP thymus ve coefficient used by the released system of model equations.
P thymus visp__thymus_Vis_ml1.09mLP thymus vis coefficient used by the released system of model equations.
P thymus vvp__thymus_Vv_ml0.353mLP thymus vv coefficient used by the released system of model equations.
Validation run noncevalidation_run_nonce0—Validation run nonce coefficient used by the released system of model equations.

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