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T-DM1 serum exposure with baseline covariates

Conditional fixed-effect T-DM1 two-compartment PK with reversible distribution, linear clearance and baseline covariate effects. Predicts serum exposure without payload release, HER2 binding, tumor response or population variability.

Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates ↗
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Reference repeated IV exposure

How do fixed covariates and repeated IV input shape typical serum exposure?

0–126 day

Study

Reference repeated IV exposure

How do fixed covariates and repeated IV input shape typical serum exposure?

Readouts

Central concentration· ug/mL
Conditional fixed-effect quantity; no source population or clinical qualification.
Cumulative AUC· mg*day/L
Conditional fixed-effect quantity; no source population or clinical qualification.
Clearance· L/day
Conditional fixed-effect quantity; no source population or clinical qualification.

Study purpose

  • Compare fixed covariate/regimen exposure; no outcome or dosing recommendation.

Interpretation limits

  • Conditional deterministic conjugated T-DM1 PK only; no original patient fit, mixed effects, VPC/NPC, bootstrap, population prediction intervals, payload release, efficacy or safety.
  • Printed rounded Table 1 coefficients are retained; Table 2 arithmetic discrepancies remain unresolved and are not acceptance targets.
  • Each starting configuration fixes six infusion amounts at 21-day intervals and 0.5-hour durations. Weight edits and scans alter disposition only; they do not recalculate doses. Select a weight-specific starting configuration to use its authored 3.6 mg/kg amounts.
  • Covariates remain fixed in time. The 0.5-hour regimen is from the source supplement, without a Figure 3 peak-reproduction claim.
  • Cumulative AUC integrates from the selected start. Interval AUC requires endpoint subtraction. The static summary marker carries no drug mass.
  • The linear model does not establish low-dose nonlinear behavior, hepatic-impairment effects or clinical validity.
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Baseline covariates

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

kg
70 → —

Serum albumin coefficient used by the released system of model equations.

g/L
41 → —

Baseline HER2 shed extracellular domain coefficient used by the released system of model equations.

ng/mL
25 → —

Baseline sum of longest target lesion dimensions coefficient used by the released system of model equations.

cm
9 → —

Serum ast coefficient used by the released system of model equations.

U/L
27 → —
Simulation time
day
day
126 → 168

Time between reported samples.

day
0.5 → 1

2 changes · Variation 1

Continue in the background and keep the result.

Biology

Conditional fixed-effect T-DM1 two-compartment PK with reversible distribution, linear clearance and baseline covariate effects. Predicts serum exposure without payload release, HER2 binding, tumor response or population variability.

Conditional fixed-effect T-DM1 two-compartment PK with reversible distribution, linear clearance and baseline covariate effects. Predicts serum exposure without payload release, HER2 binding, tumor response or population variability.
States & equation dependencies
What are the modeled states and equation-linked processes?Representative technical topology with 4 selected states: Central-compartment drug amount, Peripheral-compartment drug amount, Exposure (AUC), Summary marker. Displayed equation-linked dependencies: between Peripheral-compartment drug amount and Central-compartment drug amount; from Central-compartment drug amount to Exposure (AUC). Displayed model or scenario entry points: Administered input enters Central-compartment drug amount. There are no separately labeled equation controls.TECHNICAL TOPOLOGYWhat are the modeled states and equation-linked processes?Selected equation-linked states · model time unit: dayAdministered inputCentral-compartment drugamountmgPeripheral-compartment drugamountmgExposure (AUC)mg*day/LSummary markerdimensionless
Teal arrows show relationships between modeled states and do not always represent material transfer. Peach arrows mark administered or scenario-defined entry points.

Assumptions & evidence

Assumptions & limitations

  • Conditional deterministic conjugated T-DM1 PK only; no original patient fit, mixed effects, VPC/NPC, bootstrap, population prediction intervals, payload release, efficacy or safety.
  • Printed rounded Table 1 coefficients are retained; Table 2 arithmetic discrepancies remain unresolved and are not acceptance targets.
  • Each starting configuration fixes six infusion amounts at 21-day intervals and 0.5-hour durations. Weight edits and scans alter disposition only; they do not recalculate doses. Select a weight-specific starting configuration to use its authored 3.6 mg/kg amounts.
  • Covariates remain fixed in time. The 0.5-hour regimen is from the source supplement, without a Figure 3 peak-reproduction claim.
  • Cumulative AUC integrates from the selected start. Interval AUC requires endpoint subtraction. The static summary marker carries no drug mass.
  • The linear model does not establish low-dose nonlinear behavior, hepatic-impairment effects or clinical validity.

Parameter origins

  • Released executable model definition; exact publication locator not reported

Validation & references

One or more implementation checks are available; this is not a claim of full model reproduction.

Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates ↗

Available reference curves can be added to the plot when their scenario, readout, time and units match.

Model details

28 parameters · 4 states · 4 equations · 6 derived outputs

Classification & API access
Therapeutic
Ado-trastuzumab emtansine, trastuzumab
Modality
Antibody–drug conjugate (ADC)
Target
HER2 / ERBB2
Disease / scope
HER2-positive locally advanced or metastatic breast cancer
ParameterDefaultUnitDescription
Reference clearanceCL_ref0.676L/dayReference clearance governing removal of modeled material from the relevant compartment.
Intercompartmental clearanceQ1.534L/dayIntercompartmental clearance governing exchange between model compartments.
Reference central volumeVc_ref3.127LReference central volume used to convert modeled amount to concentration in the relevant compartment.
Peripheral distribution volumeVp0.66LPeripheral distribution volume used to convert modeled amount to concentration in the relevant compartment.
Fixed numerical guard albumin floor galbumin_floor_g_L1e-12g/LOriginal numeric floor expressed with its physical unit; not a biological control.
Serum albuminalbumin_g_L41g/LSerum albumin coefficient used by the released system of model equations.
Reference serum albuminalbumin_ref_g_L41g/LReference serum albumin coefficient used by the released system of model equations.
Serum astast_U_L27U/LSerum ast coefficient used by the released system of model equations.
Fixed numerical guard ast floor uast_floor_U_L1e-12U/LOriginal numeric floor expressed with its physical unit; not a biological control.
Reference serum astast_ref_U_L27U/LReference serum ast coefficient used by the released system of model equations.
Fixed numerical guard body weight floorbody_weight_floor_kg1kgOriginal numeric floor expressed with its physical unit; not a biological control.
Body weightbody_weight_kg70kgBody weight used for body-size scaling in the model.
Reference body weightbody_weight_ref_kg70kgReference body weight used for body-size scaling in the model.
Fixed numerical guard ecd floorecd_floor_ng_mL1e-12ng/mLOriginal numeric floor expressed with its physical unit; not a biological control.
Baseline HER2 shed extracellular domainecd_ng_mL25ng/mLBaseline HER2 shed extracellular domain coefficient used by the released system of model equations.
Reference HER2 shed extracellular domainecd_ref_ng_mL25ng/mLReference HER2 shed extracellular domain coefficient used by the released system of model equations.
Fixed eigenvalue discriminant guardeigen_discriminant_floor_day21e-121/day^2Preserves original numeric floor with inverse-day-squared unit; not a biological control.
Baseline trastuzumab concentrationtbl_ug_mL0ug/mLBaseline trastuzumab concentration coefficient used by the released system of model equations.
Albumin effect on clearancetheta_cl_albumin-0.423dimensionlessAlbumin effect on clearance governing removal of modeled material from the relevant compartment.
Ast effect on clearancetheta_cl_ast0.071dimensionlessAst effect on clearance governing removal of modeled material from the relevant compartment.
HER2 ecd effect on clearancetheta_cl_ecd0.035dimensionlessHER2 ecd effect on clearance governing removal of modeled material from the relevant compartment.
Baseline trastuzumab effect on clearancetheta_cl_tbl-0.0021/(ug/mL)Baseline trastuzumab effect on clearance governing removal of modeled material from the relevant compartment.
Target lesion burden effect on clearancetheta_cl_tmbd0.052dimensionlessTarget lesion burden effect on clearance governing removal of modeled material from the relevant compartment.
Weight effect on clearancetheta_cl_weight0.49dimensionlessWeight effect on clearance governing removal of modeled material from the relevant compartment.
Weight effect on central volumetheta_vc_weight0.596dimensionlessWeight effect on central volume used to convert modeled amount to concentration in the relevant compartment.
Baseline sum of longest target lesion dimensionstmbd_cm9cmBaseline sum of longest target lesion dimensions coefficient used by the released system of model equations.
Fixed numerical guard tmbd floor cmtmbd_floor_cm1e-12cmOriginal numeric floor expressed with its physical unit; not a biological control.
Reference target lesion burdentmbd_ref_cm9cmReference target lesion burden coefficient used by the released system of model equations.

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