Development of a population pharmacokinetic (PPK) model of intravenous (IV) trastuzumab in patients with a variety of solid tumors to support dosing and treatment recommendations.

Abstract

2525 Background: The aim of this analysis was to develop a PPK model for IV trastuzumab (Herceptin), to assess the impact of patient covariates on PK, and perform simulations to support dosing recommendations. Methods: Serum trastuzumab concentration data (26,040 samples) from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC) or other tumor types, and 6 healthy volunteers in 18 Phase I, II, and III trials were analyzed using nonlinear mixed-effects modeling (NONMEM). Monte Carlo simulations were performed using the NONMEM PK parameter estimates (with variability) to inform dosing recommendations. Results: A two-compartment model with parallel linear and nonlinear elimination best described the data. Significant covariates (P < 0.001) influencing linear CL were baseline weight, SGOT, albumin, primary tumor type, and presence of liver metastases. MBC had similar PK parameters as EBC, with lower distributions of Cmin,ss in MBC explained by covariates. The higher linear CL in AGC patients resulted in a 30.5% lower Cmin,ss. Simulations for drug washout indicated that 95% of patients with breast cancer (BC) reach trastuzumab concentrations < 1 µg/mL (~97% washout) at ≤7 months. Simulations also indicated that a missed dose of trastuzumab in BC or AGC patients of ≤1 week did not result in a long PK under-exposure (i.e. the trastuzumab concentration is within 15% of Cmin,ss by 3 weeks) but a missed dose of > 1 week took approximately 6 weeks to get back within the steady-state exposure range. Conclusions: Trastuzumab PK was well described by a two-compartment model with parallel linear and nonlinear eliminationacross cancer types, disease status, and regimens. No dose adjustment is required based on any of the identified patient covariates (e.g. weight, tumor type). Simulations using the PPK model informed the prescribing information for Herceptin; trastuzumab has a 7-month serum washout period during which patients should avoid an anthracycline-based therapy, pregnancy, or breastfeeding. A re-loading dose is required if a maintenance dose is missed by > 1 week to maintain serum concentrations.