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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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MODEL IN MOTION 18 sec

How does body weight change the T-DM1 concentration profile?

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Reference repeated IV exposure

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

0–126 day

Scenario details

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.

Assumptions

  • Models conjugated T-DM1 PK using fixed effects. Population variability, payload release, and clinical outcomes are not modeled.
  • Calculations use the rounded Table 1 coefficients. Results are conditional fixed-effect trajectories, not a reconstruction of the original patient-level fit, population uncertainty or source sensitivity table.
  • Each configuration fixes six 30-minute infusions, 21 days apart. Weight edits change disposition only; choose a weight-specific configuration for its 3.6 mg/kg doses.
  • Covariates stay fixed. The 30-minute infusion schedule comes from the supplement; Figure 3 peaks have not been reproduced.
  • Cumulative AUC starts at the selected start; interval AUC requires endpoint subtraction. The summary marker adds no drug.
  • This linear model does not represent low-dose nonlinearity or hepatic impairment.

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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

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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.

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/day²Preserves original numeric floor with inverse-day-squared unit; not a biological control.
Baseline trastuzumab concentrationtbl_ug_mL0µg/mLBaseline trastuzumab concentration coefficient used by the released system of model equations.
Albumin effect on clearancetheta_cl_albumin-0.423—Albumin effect on clearance governing removal of modeled material from the relevant compartment.
Ast effect on clearancetheta_cl_ast0.071—Ast effect on clearance governing removal of modeled material from the relevant compartment.
HER2 ecd effect on clearancetheta_cl_ecd0.035—HER2 ecd effect on clearance governing removal of modeled material from the relevant compartment.
Baseline trastuzumab effect on clearancetheta_cl_tbl-0.0021/(µg/mL)Baseline trastuzumab effect on clearance governing removal of modeled material from the relevant compartment.
Target lesion burden effect on clearancetheta_cl_tmbd0.052—Target lesion burden effect on clearance governing removal of modeled material from the relevant compartment.
Weight effect on clearancetheta_cl_weight0.49—Weight effect on clearance governing removal of modeled material from the relevant compartment.
Weight effect on central volumetheta_vc_weight0.596—Weight 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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