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Zenocutuzumab PK and tumor-growth dynamics

A translational PK/PD model coupling zenocutuzumab distribution and nonlinear clearance to concentration-dependent tumor-cell death and net tumor-volume dynamics.

Translational PK-PD modeling analysis of MCLA-128, a HER2/HER3 bispecific monoclonal antibody, to predict clinical efficacious exposure and dose ↗

Investigational New Drugs

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MODEL IN MOTION 18 sec

How does the mouse dose change drug amount and tumor dynamics?

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Human 360 mg every 3 weeks receptor occupancy

How does zenocutuzumab exposure translate into tumor-growth inhibition over time?

0–504 hour

Scenario details

Human 360 mg every 3 weeks receptor occupancy

How does zenocutuzumab exposure translate into tumor-growth inhibition over time?

Readouts

Central zenocutuzumab concentration · Unit unavailable
Central zenocutuzumab concentration over the selected simulation window.
Peripheral zenocutuzumab concentration · Unit unavailable
Peripheral zenocutuzumab concentration over the selected simulation window.
Tumor volume · millimeter**3
Tumor volume over the selected simulation window.
Drug modified tumor growth · dimensionless
Drug modified tumor growth over the selected simulation window.
Exposure (AUC) · mg*h/L
Exposure (AUC) over the selected simulation window.

Study purpose

  • How does zenocutuzumab exposure translate into tumor-growth inhibition over time?

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Model parameter

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

L/h

Suggested: 0.00625–0.0188. You can explore beyond this range.

0.0125 → —

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

L

Suggested: 1.59–4.76. You can explore beyond this range.

3.17 → —

Maximum elimination rate coefficient used by the released system of model equations.

mg/h

Suggested: 0.25–0.75. You can explore beyond this range.

0.5 → —

Michaelis constant coefficient used by the released system of model equations.

mg/L

Suggested: 0.11–0.329. You can explore beyond this range.

0.219 → —

Tumor-kill half-maximal concentration at which the corresponding modeled effect reaches half of its maximum.

mg/L

Suggested: 5.10e-6–1.53e-5. You can explore beyond this range.

0.0000102 → —
Simulation time
h
h
504 → 168

Time between reported samples.

h
24 → 1

2 changes · Variation 1

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Biology

Intravenous zenocutuzumab enters a central pool, exchanges with a peripheral pool, and undergoes linear and saturable elimination. Central concentration separately lowers a tumor-growth drive and raises a tumor-death drive, which together change tumor volume.

How does zenocutuzumab exposure change empirical tumor growth and death drives?Intravenous zenocutuzumab enters a central pool, exchanges with a peripheral pool, and undergoes linear and saturable elimination. Central concentration separately lowers a tumor-growth drive and raises a tumor-death drive, which together change tumor volume.BIOLOGY OVERVIEWHow does zenocutuzumab exposure change empirical tumor growth and death drives?IV zenocutuzumab: Dose to central compartmentIV zenocutuzumabDose to central compartmentCentral exposure: Zenocutuzumab concentrationCentral exposureZenocutuzumab concentrationPeripheral pool: Reversible distributionPeripheral poolReversible distributionPK elimination: Linear and saturable lossPK eliminationLinear and saturable lossGrowth drive: Exposure lowers tumor growthGrowth driveExposure lowers tumor growthDeath drive: Exposure raises tumor lossDeath driveExposure raises tumor lossTumor volume: Net empirical tumor responseTumor volumeNet empirical tumor responsePRIMARY READOUTSCentral zenocutuzumab concentrationCentral zenocutuzumab conc…Peripheral concentrationPeripheral concentrationTumor volumeTumor volumeGrowth effectGrowth effectCumulative exposureCumulative exposure

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

Model scope: HER2/HER3 binding, receptor occupancy or signaling, immune-effector killing, and target-mediated clearance are not represented; tumor pharmacodynamics are empirical exposure effects.

Modeled relationships (7)
  • IV zenocutuzumab → Central exposure: IV input (flow)
  • Central exposure ↔ Peripheral pool: distribution (reversible exchange)
  • Central exposure → PK elimination: linear + saturable (loss)
  • Central exposure → Growth drive: inhibits growth (modulation)
  • Growth drive → Tumor volume: growth contribution (production)
  • Central exposure → Death drive: stimulates death (modulation)
  • Death drive → Tumor volume: tumor loss (loss)

Modeled relationships: IV zenocutuzumab to Central exposure: IV input (flow); Central exposure reversibly exchanges with Peripheral pool: distribution (reversible exchange); Central exposure to PK elimination: linear + saturable (loss); Central exposure to Growth drive: inhibits growth (modulation); Growth drive to Tumor volume: growth contribution (production); Central exposure to Death drive: stimulates death (modulation); Death drive to Tumor volume: tumor loss (loss).

Primary readouts: Central zenocutuzumab concentration; Peripheral concentration; Tumor volume; Growth effect; Cumulative exposure.

Model details

14 parameters · 6 states · 6 equations · 12 derived outputs

Classification & API access
Therapeutic
Zenocutuzumab
Modality
Bispecific antibody / T-cell engager
Target
ERBB3, HER3, HER2 / ERBB2
Disease / scope
HER2/HER3-driven preclinical tumors and first-in-human translation
ParameterDefaultUnitDescription
Systemic clearanceCL_L_h0.0125L/hSystemic clearance governing removal of modeled material from the relevant compartment.
Tumor-kill half-maximal concentrationEC50_KD_mg_L0.0000102mg/LTumor-kill half-maximal concentration at which the corresponding modeled effect reaches half of its maximum.
EC50 kioEC50_Kio_mg_L2.6mg/LEC50 kio at which the corresponding modeled effect reaches half of its maximum.
Maximum effectEmax1—Maximum effect defining the limiting magnitude of the corresponding pharmacodynamic effect.
Dissociation constantKD_1_h0.0041/hDissociation constant describing equilibrium binding affinity in the modeled interaction.
Tumor growth coefficientKG_mm3_h0.338(mm³)/hTumor growth coefficient coefficient used by the released system of model equations.
KioKio_1_h0.1431/hKio coefficient used by the released system of model equations.
Michaelis constantKm_mg_L0.219mg/LMichaelis constant coefficient used by the released system of model equations.
Intercompartmental clearanceQ_L_h0.0313L/hIntercompartmental clearance governing exchange between model compartments.
Central distribution volumeV1_L3.17LCentral distribution volume used to convert modeled amount to concentration in the relevant compartment.
Peripheral distribution volumeV2_L3.51LPeripheral distribution volume used to convert modeled amount to concentration in the relevant compartment.
Maximum elimination rateVmax_mg_h0.5mg/hMaximum elimination rate coefficient used by the released system of model equations.
Drug stimulated death scaledrug_stimulated_death_scale1—Drug stimulated death scale coefficient used by the released system of model equations.
Progression factorprogression_factor_1_week0.1721/weekProgression factor coefficient used by the released system of model equations.

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