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Dabigatran–idarucizumab reversal during cardiopulmonary bypass

A PK/PD model coupling dabigatran systemic and bypass-circuit disposition to effect-site concentration and idarucizumab exposure during cardiopulmonary bypass.

Dabigatran-idarucizumab pharmacokinetics-pharmacodynamics in sheep undergoing cardiopulmonary bypass ↗

Perfusion

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MODEL IN MOTION 18 sec

How does the reversal intervention reshape the effect-site signal?

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Starting example

CPB dabigatran and idarucizumab reversal

CPB dabigatran and idarucizumab reversal

How do bypass-circuit exchange and idarucizumab exposure change dabigatran concentration and effect-site reversal? Explore this biological starting configuration through Central dabigatran concentration, Dabigatran effect-site concentration, Bypass-circuit dabigatran concentration, Idarucizumab concentration, Mean bypass dabigatran concentration.

0–1,440 minute

Scenario details

CPB dabigatran and idarucizumab reversal

How do bypass-circuit exchange and idarucizumab exposure change dabigatran concentration and effect-site reversal? Explore this biological starting configuration through Central dabigatran concentration, Dabigatran effect-site concentration, Bypass-circuit dabigatran concentration, Idarucizumab concentration, Mean bypass dabigatran concentration.

Readouts

Central dabigatran concentration · Unit unavailable
Central dabigatran concentration over the selected simulation window.
Effect-site concentration · mg/L
Effect-site concentration over the selected simulation window.
Bypass circuit dabigatran concentration · Unit unavailable
Bypass circuit dabigatran concentration over the selected simulation window.
Idarucizumab concentration · Unit unavailable
Idarucizumab concentration over the selected simulation window.
Mean bypass dabigatran concentration · Unit unavailable
Mean bypass dabigatran concentration over the selected simulation window.

Study purpose

  • How do bypass-circuit exchange and idarucizumab exposure change dabigatran concentration and effect-site reversal?

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Model parameter

Standardized systemic clearance governing removal of modeled material from the relevant compartment.

L/minute

Suggested: 0.0255–0.0764. You can explore beyond this range.

0.0509 → —

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

L

Suggested: 1.95–5.84. You can explore beyond this range.

3.89 → —

Circuit flow rate coefficient used by the released system of model equations.

L/min

Suggested: 0.91–2.73. You can explore beyond this range.

1.82 → —

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

L/min

Suggested: 0.0197–0.0591. You can explore beyond this range.

0.0394 → —

Idarucizumab loading dose defining the modeled treatment input for the explored scenario.

mg/kg

Suggested: 25–75. You can explore beyond this range.

50 → —
Simulation time
minute
minute
1440 → 168

Time between reported samples.

minute

1 change · Variation 1

Continue in the background and keep the result.

Biology

A timed protocol independently supplies dabigatran and idarucizumab. Dabigatran distributes between central, peripheral, and CPB-circuit pools and equilibrates with an effect-site concentration. Idarucizumab has separate exposure and clearance; the released equations do not couple it to dabigatran or the effect site.

How do protocol-driven dabigatran and idarucizumab exposures evolve during CPB?A timed protocol independently supplies dabigatran and idarucizumab. Dabigatran distributes between central, peripheral, and CPB-circuit pools and equilibrates with an effect-site concentration. Idarucizumab has separate exposure and clearance; the released equations do not couple it to dabigatran or the effect site.BIOLOGY OVERVIEWHow do protocol-driven dabigatran and idarucizumab exposures evolve during CPB?Timed protocol inputs: Separate drug-rate schedulesTimed protocolinputsSeparate drug-rate schedulesCentral dabigatran: Systemic exposureCentral dabigatranSystemic exposurePeripheral dabigatran: Reversible distributionPeripheraldabigatranReversible distributionCPB circuit pool: Gated pump exchangeCPB circuit poolGated pump exchangeEffect-site concentration: Equilibrates with central drugEffect-siteconcentrationEquilibrates with central drugIdarucizumab exposure: Independent modeled amountIdarucizumabexposureIndependent modeled amountSeparate clearances: No modeled neutralization couplingSeparateclearancesNo modeled neutralizationcouplingPRIMARY READOUTSDabigatran concentrationDabigatran concentrationEffect-site concentrationEffect-site concentrationCPB circuit concentrationCPB circuit concentrationIdarucizumab concentrationIdarucizumab concentrationCPB mean dabigatranCPB mean dabigatran

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

Model scope: Idarucizumab binding or neutralization of dabigatran, an idarucizumab-to-effect-site influence, coagulation, and a reaction-time response are not present in the released equations.

Modeled relationships (7)
  • Timed protocol inputs → Central dabigatran: dabigatran rates (flow)
  • Timed protocol inputs → Idarucizumab exposure: idarucizumab rates (flow)
  • Central dabigatran ↔ Peripheral dabigatran: distribution (reversible exchange)
  • Central dabigatran ↔ CPB circuit pool: CPB exchange (reversible exchange)
  • Central dabigatran → Effect-site concentration: equilibration (modulation)
  • Central dabigatran → Separate clearances: dabigatran CL (loss)
  • Idarucizumab exposure → Separate clearances: idarucizumab CL (loss)

Modeled relationships: Timed protocol inputs to Central dabigatran: dabigatran rates (flow); Timed protocol inputs to Idarucizumab exposure: idarucizumab rates (flow); Central dabigatran reversibly exchanges with Peripheral dabigatran: distribution (reversible exchange); Central dabigatran reversibly exchanges with CPB circuit pool: CPB exchange (reversible exchange); Central dabigatran to Effect-site concentration: equilibration (modulation); Central dabigatran to Separate clearances: dabigatran CL (loss); Idarucizumab exposure to Separate clearances: idarucizumab CL (loss).

Primary readouts: Dabigatran concentration; Effect-site concentration; CPB circuit concentration; Idarucizumab concentration; CPB mean dabigatran.

Model details

24 parameters · 7 states · 7 equations · 58 derived outputs

Classification & API access
Therapeutic
Dabigatran and idarucizumab
Modality
Antibody fragment
Target
Thrombin, Dabigatran
Disease / scope
Preclinical anticoagulation reversal during cardiopulmonary bypass
ParameterDefaultUnitDescription
Body weightbody_weight_kg25.98kgBody weight used for body-size scaling in the model.
Idarucizumab clearancecl_ida_l_min0.0394L/minIdarucizumab clearance governing removal of modeled material from the relevant compartment.
Standardized systemic clearancecl_std_l_min_70kg0.0509L/minuteStandardized systemic clearance governing removal of modeled material from the relevant compartment.
Cpb endcpb_end_min120minCpb end coefficient used by the released system of model equations.
Dab high enddab_high_end_min30minuteDab high end coefficient used by the released system of model equations.
Dab high ratedab_high_rate_mg_kg_min0.0175mg/kg/minDab high rate coefficient used by the released system of model equations.
Dab loading durationdab_loading_duration_min1minuteDab loading duration defining the modeled treatment input for the explored scenario.
Dab loadingdab_loading_mg_kg0.25mg/kgDab loading defining the modeled treatment input for the explored scenario.
Dab low ratedab_low_rate_mg_kg_min0.0075mg/kg/minDab low rate coefficient used by the released system of model equations.
Circuit flow rateflow_l_min1.82L/minCircuit flow rate coefficient used by the released system of model equations.
FV2 cpbfv2_cpb2.25—FV2 cpb coefficient used by the released system of model equations.
Idarucizumab loading durationida_loading_duration_min0.5minIdarucizumab loading duration defining the modeled treatment input for the explored scenario.
Idarucizumab loading doseida_loading_mg_kg50mg/kgIdarucizumab loading dose defining the modeled treatment input for the explored scenario.
Idarucizumab maintenance durationida_maintenance_duration_min60minIdarucizumab maintenance duration coefficient used by the released system of model equations.
Idarucizumab maintenanceida_maintenance_mg_kg50mg/kgIdarucizumab maintenance coefficient used by the released system of model equations.
Population Q3 flow factorpop_q3_flow_factor1—Population Q3 flow factor coefficient used by the released system of model equations.
Protocol enabledprotocol_enabled0—Protocol enabled coefficient used by the released system of model equations.
Pump volumepump_volume_l0.45LPump volume used to convert modeled amount to concentration in the relevant compartment.
Standardized intercompartmental clearanceq_std_l_min_70kg0.229L/minuteStandardized intercompartmental clearance governing exchange between model compartments.
Reference weightreference_weight_kg70kgReference weight coefficient used by the released system of model equations.
Teq half timeteq_half_time_min0.011minTeq half time coefficient used by the released system of model equations.
Standardized central distribution volumev1_std_l_70kg3.89LStandardized central distribution volume used to convert modeled amount to concentration in the relevant compartment.
Distribution volume 2 standardizedv2_std_l_70kg11.4LDistribution volume 2 standardized used to convert modeled amount to concentration in the relevant compartment.
V idarucizumabv_ida_l6.47LV idarucizumab coefficient used by the released system of model equations.

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