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Trastuzumab exposure after subcutaneous and IV dosing

Conditional two-compartment trastuzumab PK with SC absorption, reversible distribution, parallel linear and saturable elimination, and fixed weight/ALT effects. No population, efficacy or safety prediction.

Population pharmacokinetic and exposure–response analysis for trastuzumab administered using a subcutaneous “manual syringe” injection or intravenously in women with HER2-positive early breast cancer ↗
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Fixed 600 mg SC every three weeks

How does this fixed-effect regimen change serum antibody exposure with parallel linear and saturable elimination?

0–147 day

Study

Fixed 600 mg SC every three weeks

How does this fixed-effect regimen change serum antibody exposure with parallel linear and saturable elimination?

Readouts

Central serum antibody concentration· ug/mL
Central amount divided by effective central volume; mg/L is numerically equivalent to ug/mL.
Exposure (AUC)· ug*day/mL
Integral since simulation start. Subtract interval endpoints before describing an interval AUC.
Saturable antibody elimination· mg/day
Michaelis-Menten amount loss; this reduced system does not represent an observed receptor state.

Study purpose

  • What exposure follows this regimen under the same fixed covariates?

Interpretation limits

  • Fixed-effect PK exploration for the source early-breast-cancer context; no individual, stochastic population, VPC or estimation reproduction.
  • SC doses enter the depot as boluses, approximating the source five-minute SC administration; IV loading/maintenance durations are retained explicitly.
  • Body weight and ALT are fixed covariates. Fixed SC dosing and weight-scaled IV regimens compare different dose policies, not route alone.
  • Cumulative AUC starts at the simulation origin. AUC over a dosing interval requires endpoint subtraction.
  • The reported source IV Cmax values agree with an inferred half-day sampling grid, while true infusion-end peaks differ. Source sampling-grid authority remains unresolved.
  • The local concentration-dependent elimination half-time is not a terminal disposition half-life for this nonlinear system.
  • No pCR, adverse-event, clinical benefit, safety, target-occupancy or dose-recommendation prediction. The separate descriptive exposure-response coefficients remain private source context.
  • Original 15,761 observations, individual covariates, covariance matrices, likelihoods, empirical Bayes estimates and bootstrap/VPC outputs are unavailable.
  • Editing or scanning body weight changes disposition only and preserves every selected dose amount. IV amounts are authored for 68 kg and are not recalculated.
  • Joint weight/ALT combinations are deterministic explorations within observed marginal ranges, not validated population combinations.
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Baseline covariates

Body weight. Fixed-effect PK quantity; source scientific provenance retained separately.

kg
68 → —

Alanine transaminase. Fixed-effect PK quantity; source scientific provenance retained separately.

IU/L
19 → —
Simulation time
day
day
147 → 168

Time between reported samples.

day
0.5 → 1

2 changes · Variation 1

Continue in the background and keep the result.

Biology

Conditional two-compartment trastuzumab PK with SC absorption, reversible distribution, parallel linear and saturable elimination, and fixed weight/ALT effects. No population, efficacy or safety prediction.

Conditional two-compartment trastuzumab PK with SC absorption, reversible distribution, parallel linear and saturable elimination, and fixed weight/ALT effects. No population, efficacy or safety prediction.
States & equation dependencies
What are the modeled states and equation-linked processes?Representative technical topology with 5 selected states: Administration-site drug amount, Central-compartment drug amount, Peripheral-compartment drug amount, Exposure (AUC), Elapsed time. Displayed equation-linked dependencies: from Administration-site drug amount to Central-compartment drug amount; 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 Administration-site 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 inputAdministration-site drugamountmgCentral-compartment drugamountmgPeripheral-compartment drugamountmgExposure (AUC)ug*day/mLElapsed timeday
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

  • Fixed-effect PK exploration for the source early-breast-cancer context; no individual, stochastic population, VPC or estimation reproduction.
  • SC doses enter the depot as boluses, approximating the source five-minute SC administration; IV loading/maintenance durations are retained explicitly.
  • Body weight and ALT are fixed covariates. Fixed SC dosing and weight-scaled IV regimens compare different dose policies, not route alone.
  • Cumulative AUC starts at the simulation origin. AUC over a dosing interval requires endpoint subtraction.
  • The reported source IV Cmax values agree with an inferred half-day sampling grid, while true infusion-end peaks differ. Source sampling-grid authority remains unresolved.
  • The local concentration-dependent elimination half-time is not a terminal disposition half-life for this nonlinear system.
  • No pCR, adverse-event, clinical benefit, safety, target-occupancy or dose-recommendation prediction. The separate descriptive exposure-response coefficients remain private source context.
  • Original 15,761 observations, individual covariates, covariance matrices, likelihoods, empirical Bayes estimates and bootstrap/VPC outputs are unavailable.
  • Editing or scanning body weight changes disposition only and preserves every selected dose amount. IV amounts are authored for 68 kg and are not recalculated.
  • Joint weight/ALT combinations are deterministic explorations within observed marginal ranges, not validated population combinations.

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 pharmacokinetic and exposure–response analysis for trastuzumab administered using a subcutaneous “manual syringe” injection or intravenously in women with HER2-positive early breast cancer ↗

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

Model details

21 parameters · 5 states · 5 equations · 11 derived outputs

Classification & API access
Therapeutic
Trastuzumab
Modality
Monoclonal antibody
Target
HER2 / ERBB2
Disease / scope
HER2-positive early breast cancer, HannaH trial SC manual syringe versus IV trastuzumab
ParameterDefaultUnitDescription
Alanine transaminaseALT_IU_L19IU/LAlanine transaminase. Fixed-effect PK quantity; source scientific provenance retained separately.
Alt floor iuALT_floor_IU_L0.1IU/LFixed physical unit for the unchanged existing numerical guard; not an analysis control.
Systemic clearanceCL_L_day0.111L/dayLinear clearance. Fixed-effect PK quantity; source scientific provenance retained separately.
Subcutaneous bioavailabilityF_sc0.771dimensionlessSC bioavailability. Fixed-effect PK quantity; source scientific provenance retained separately.
Michaelis constantKm_mg_L33.9mg/LMichaelis-Menten concentration. Fixed-effect PK quantity; source scientific provenance retained separately.
Intercompartmental clearanceQ_L_day0.445L/dayIntercompartmental clearance. Fixed-effect PK quantity; source scientific provenance retained separately.
Central distribution volumeVc_L2.91LCentral volume. Fixed-effect PK quantity; source scientific provenance retained separately.
Maximum nonlinear elimination rateVmax_mg_day11.9mg/dayMaximum nonlinear elimination rate. Fixed-effect PK quantity; source scientific provenance retained separately.
Peripheral distribution volumeVp_L3.06LPeripheral volume. Fixed-effect PK quantity; source scientific provenance retained separately.
Amount flooramount_floor_mg0mgFixed physical unit for the unchanged existing numerical guard; not an analysis control.
Body weightbody_weight_kg68kgBody weight. Fixed-effect PK quantity; source scientific provenance retained separately.
Clearance floorclearance_floor_L_day1e-9L/dayFixed physical unit for the unchanged existing numerical guard; not an analysis control.
Concentration floorconcentration_floor_mg_L1e-9mg/LFixed physical unit for the unchanged existing numerical guard; not an analysis control.
Absorption rate constantka_1_day0.4041/dayFirst-order SC absorption rate. Fixed-effect PK quantity; source scientific provenance retained separately.
Reference altreference_ALT_IU_L19IU/LReference ALT. Fixed-effect PK quantity; source scientific provenance retained separately.
Reference body weightreference_weight_kg68kgReference body weight. Fixed-effect PK quantity; source scientific provenance retained separately.
Alt exponent on clearancetheta_alt_CL0.144dimensionlessALT exponent on CL. Fixed-effect PK quantity; source scientific provenance retained separately.
Body weight exponent on clearancetheta_wt_CL1.04dimensionlessBody-weight exponent on CL. Fixed-effect PK quantity; source scientific provenance retained separately.
Body weight exponent on central distribution volumetheta_wt_Vc0.443dimensionlessBody-weight exponent on Vc. Fixed-effect PK quantity; source scientific provenance retained separately.
Body weight exponent on peripheral distribution volumetheta_wt_Vp0.5dimensionlessBody-weight exponent on Vp. Fixed-effect PK quantity; source scientific provenance retained separately.
Weight floorweight_floor_kg1kgFixed physical unit for the unchanged existing numerical guard; not an analysis control.

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