Abstract

PURPOSE:
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC).

METHODS:
Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling. The influence of demographic, baseline laboratory, and disease characteristics on T-DM1 PK was examined.

RESULTS:
T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. The final population model estimated linear clearance (CL) of 0.79 L/day, volume of distribution in the central compartment (V c) of 4.48 L, distribution clearance (Q) of 0.62 L/day, volume of distribution in the peripheral compartment (V p) of 1.49 L, nonlinear CL of 2.06 L/day, and KM of 1.63 μg/mL. Parameter uncertainty was low to moderate for fixed effects, except KM (estimated with poor precision). Patients with high body weight and low baseline trastuzumab concentrations had significantly faster linear CL; those with higher body weight had significantly larger V c.

CONCLUSIONS:
In a HER2-positive AGC population, T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Baseline body weight and trastuzumab concentration were identified as significant covariates for T-DM1 PK in a HER2-positive AGC population.