Toxicity sets the dose, not efficacy. Dose-limiting toxicity is a binary readout in a short early window [1,2]. For cytotoxics, neutropenia is the continuous alternative, captured by semi-mechanistic myelosuppression models with a proliferating compartment, maturation transit compartments and a feedback term [3,4].
Efficacy is modeled in two steps. A longitudinal tumor size model (RECIST sum of diameters) balances drug-driven shrinkage against regrowth [5,6]; quantities derived from it feed a time-to-event analysis of survival [7,8]. That is what lets early imaging inform an endpoint reading out much later [9,10].
Antibodies are nonlinear where it matters. Target-mediated drug disposition makes binding itself an elimination pathway that saturates [11,12], so a model fitted only to the top of the dose range will mislead at the bottom [13]. Antibody-drug conjugates add conjugate, total antibody and payload as separate analytes [14,15].
Cell therapies replace PK with cellular kinetics. A living product expands, contracts and persists [16,17], and the administered dose is a weak predictor of the exposure that follows [18].
Covariates carrying dosing guidance. DPYD for fluoropyrimidines, TPMT and NUDT15 for thiopurines, UGT1A1 for irinotecan, CYP2D6 for tamoxifen [19,20].
CAR T cell therapy
Emily Whitehead, the first child treated with CD19-directed CAR T cells for refractory acute lymphoblastic leukemia, entered a durable complete remission [21].
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