Method Profile
A two-clone tumor model links ADC and free-payload disposition with tumor–immune dynamics, using trial-response data to constrain virtual cohorts.
Interrogate how antigen-linked delivery, systemically released SN-38 and intrinsic payload sensitivity contribute under the model assumptions.
Four-compartment TNBC QSP model with antigen-high and antigen-low clones whose SN-38 sensitivities also differ.
Simulate sacituzumab govitecan at 10 mg/kg on days 1 and 8 of each 21-day cycle; sample 34 parameters and compare cohort response categories.
Pharmacology and clone inputs
Published sacituzumab govitecan/SN-38 disposition and response data; TROP2-high/low clone-specific potency and cytotoxicity assumptions.
Clinical references
Phase I/II basket-trial response categories for calibration and ASCENT categories for a separate comparison.
Separate antigen expression from its modeled covariation with payload sensitivity; compare free-payload transport enabled versus disabled rather than attributing a correlation to targeted delivery.
Calibrate virtual response categories, compare a distinct phase III dataset without recalibration, then perturb payload transport and clone fractions.
400 initial calibration virtual patients; 244 evaluable virtual patients for comparison confidence intervals; 1,200 starting virtual patients for later stability-based sensitivity analyses, subject to initial tumor-size exclusion.
Published phase I/II and ASCENT response categories; matched model simulations with and without plasma-to-tumor free SN-38 permeability.
Predicted partial/complete response 33.2% versus clinical 34.0%; stable disease 38.5% versus 39.3%; progressive disease 28.3% versus 26.6%. Targeted delivery alone contributes approximately 2.4%/0.4% of total intracellular exposure in high/low clones under this model.
A quantitative systems pharmacology model of sacituzumab govitecan reproduces trial-level response patterns in triple-negative breast cancer. Its simulations attribute much of the modeled effect to circulating SN-38 and clone-specific payload sensitivity.
