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ABSTRCT
PURPOSE:
Trastuzumab emtansine (TDM1) is an antibody drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of TDM1 PK parameters and the effects of clinically relevant covariates.

METHODS:
Serum samples were collected from 671 patients with human epidermal growth factor receptor 2 positive locally advanced or metastatic breast cancer (MBC) who received single-agent TDM1 in five phase I to phase III studies. Nonlinear mixed effects modeling with the first-order conditional estimation method was used.

RESULTS:
A linear two compartment model with first-order elimination from the central compartment described TDM1 PKs in the clinical dose range. TDM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (V c) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence TDM1 PK. Given the low-to-moderate effect of all statistically significant covariates on TDM1 exposure, none of these covariates is expected to result in a clinically meaningful change in TDM1 exposure.

CONCLUSIONS:
TDM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC.