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Befovacimab PK and TFPI target binding

A QSS-TMDD model representing intravenous or subcutaneous befovacimab disposition, TFPI turnover, free antibody, and antibody–TFPI complex dynamics.

Mechanistic Modeling of the Pharmacodynamic and Pharmacokinetic Relationship of Tissue Factor Pathway Inhibitor-Neutralizing Antibody (BAY 1093884) in Cynomolgus Monkeys ↗

The AAPS Journal

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MODEL IN MOTION 18 sec

How does increasing the IV dose change drug amount and target turnover?

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cynomolgus IV 5 mg/kg QSS-TMDD

How do route and dose change befovacimab exposure, free antibody, TFPI, and bound complex? Explore this biological starting configuration through Total central befovacimab, Free central befovacimab, Total TFPI, Befovacimab–TFPI complex, Cumulative exposure.

0–720 hour

Scenario details

cynomolgus IV 5 mg/kg QSS-TMDD

How do route and dose change befovacimab exposure, free antibody, TFPI, and bound complex? Explore this biological starting configuration through Total central befovacimab, Free central befovacimab, Total TFPI, Befovacimab–TFPI complex, Cumulative exposure.

Readouts

Total central befovacimab · Unit unavailable
Total central befovacimab over the selected simulation window.
Free central befovacimab · Unit unavailable
Free central befovacimab over the selected simulation window.
Total target concentration · nM
Total target concentration over the selected simulation window.
Befovacimab TFPI complex · Unit unavailable
Befovacimab TFPI complex over the selected simulation window.
Exposure (AUC) · mg*h/L
Exposure (AUC) over the selected simulation window.

Study purpose

  • How do route and dose change befovacimab exposure, free antibody, TFPI, and bound complex?

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Model parameter

Systemic clearance governing removal of modeled material from the relevant compartment.

L/h/kg

Suggested: 1.43e-4–4.31e-4. You can explore beyond this range.

0.000287 → —

Central distribution volume used to convert modeled amount to concentration in the relevant compartment.

L/kg

Suggested: 0.0246–0.0737. You can explore beyond this range.

0.0491 → —

Quasi-steady-state binding constant describing equilibrium binding affinity in the modeled interaction.

nM

Suggested: 116–348. You can explore beyond this range.

232 → —

Target internalization rate coefficient used by the released system of model equations.

1/h

Suggested: 27.7–83.1. You can explore beyond this range.

55.4 → —

Target synthesis rate governing production or formation in the modeled biological process.

nM/h

Suggested: 1.3–3.9. You can explore beyond this range.

2.6 → —
Simulation time
h
h
720 → 168

Time between reported samples.

h

1 change · Variation 1

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Biology

A scenario initializes intravenous central befovacimab or fast and delayed subcutaneous depots. Absorbed antibody enters central total-drug disposition and exchanges as free antibody with a peripheral pool. TFPI is synthesized and turned over, while an algebraic QSS allocation determines antibody-TFPI complex and its internalization.

How do IV or subcutaneous befovacimab entry, TFPI turnover, and QSS binding interact?A scenario initializes intravenous central befovacimab or fast and delayed subcutaneous depots. Absorbed antibody enters central total-drug disposition and exchanges as free antibody with a peripheral pool. TFPI is synthesized and turned over, while an algebraic QSS allocation determines antibody-TFPI complex and its internalization.BIOLOGY OVERVIEWHow do IV or subcutaneous befovacimab entry, TFPI turnover, and QSS bindinginteract?Route initialization: IV central or SC depot statesRouteinitializationIV central or SC depot statesFast + delayed SC depots: Route-specific absorptionFast + delayed SCdepotsRoute-specific absorptionBefovacimab disposition: Central total/free and peripheral freeBefovacimabdispositionCentral total/free andperipheral freeTFPI synthesis: Baseline production and turnoverTFPI synthesisBaseline production andturnoverTotal TFPI: Dynamic target poolTotal TFPIDynamic target poolQSS antibody–TFPI complex: Algebraic binding allocationQSS antibody–TFPIcomplexAlgebraic binding allocationDrug + target removal: Linear CL, turnover, internalizationDrug + targetremovalLinear CL, turnover,internalizationPRIMARY READOUTSCentral total antibodyCentral total antibodyCentral free antibodyCentral free antibodyTotal TFPITotal TFPIAntibody–TFPI complexAntibody–TFPI complexCumulative exposureCumulative exposure

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

Model scope: Kinetic association/dissociation states, coagulation-cascade dynamics, thrombin generation, bleeding outcomes, and modeled dose events are not represented; public routes initialize states and binding is algebraic QSS.

Modeled relationships (9)
  • Route initialization → Fast + delayed SC depots: SC initialization (flow)
  • Route initialization → Befovacimab disposition: IV initialization (flow)
  • Fast + delayed SC depots → Befovacimab disposition: absorption (flow)
  • TFPI synthesis → Total TFPI: target synthesis (production)
  • Befovacimab disposition → QSS antibody–TFPI complex: QSS allocation (modulation)
  • Total TFPI → QSS antibody–TFPI complex: QSS allocation (modulation)
  • Befovacimab disposition → Drug + target removal: free-drug CL (loss)
  • Total TFPI → Drug + target removal: target turnover (loss)
  • QSS antibody–TFPI complex → Drug + target removal: internalization (loss)

Modeled relationships: Route initialization to Fast + delayed SC depots: SC initialization (flow); Route initialization to Befovacimab disposition: IV initialization (flow); Fast + delayed SC depots to Befovacimab disposition: absorption (flow); TFPI synthesis to Total TFPI: target synthesis (production); Befovacimab disposition to QSS antibody–TFPI complex: QSS allocation (modulation); Total TFPI to QSS antibody–TFPI complex: QSS allocation (modulation); Befovacimab disposition to Drug + target removal: free-drug CL (loss); Total TFPI to Drug + target removal: target turnover (loss); QSS antibody–TFPI complex to Drug + target removal: internalization (loss).

Primary readouts: Central total antibody; Central free antibody; Total TFPI; Antibody–TFPI complex; Cumulative exposure.

Model details

12 parameters · 8 states · 8 equations · 25 derived outputs

Classification & API access
Therapeutic
Befovacimab, BAY 1093884 / befovacimab
Modality
Monoclonal antibody
Target
TFPI, tissue factor pathway inhibitor
Disease / scope
Translational hemophilia prophylaxis
ParameterDefaultUnitDescription
Systemic clearancecl_L_h_kg0.000287L/h/kgSystemic clearance governing removal of modeled material from the relevant compartment.
Cldcld_L_h_kg0.000645L/h/kgCld coefficient used by the released system of model equations.
Degradation ratekdeg_h4.111/hDegradation rate governing loss, degradation, or removal in the modeled biological process.
Target internalization ratekint_h55.41/hTarget internalization rate coefficient used by the released system of model equations.
Quasi-steady-state binding constantkss_nM232nMQuasi-steady-state binding constant describing equilibrium binding affinity in the modeled interaction.
Target synthesis rateksyn_nM_h2.6nM/hTarget synthesis rate governing production or formation in the modeled biological process.
NnM_per_mg_L6.6666666667nM/(mg/L)N coefficient used by the released system of model equations.
Subcutaneous fast absorption ratesc_fast_ka_h31/hSubcutaneous fast absorption rate governing entry from the administration site.
Subcutaneous slow KA1sc_slow_ka1_h0.0241/hSubcutaneous slow KA1 coefficient used by the released system of model equations.
Subcutaneous slow KA2sc_slow_ka2_h0.121/hSubcutaneous slow KA2 coefficient used by the released system of model equations.
Central distribution volumevc_L_kg0.0491L/kgCentral distribution volume used to convert modeled amount to concentration in the relevant compartment.
Vtvt_L_kg0.0606L/kgVt coefficient used by the released system of model equations.

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