Abstract
PurposeThe aim of the study was to characterize the population pharmacokinetics (PK) of the intravenous formulation of trastuzumab, assess the impact of patient and pathological covariates on trastuzumab PK, and perform simulations to support dosing recommendations in special situations.MethodsSerum trastuzumab concentrations were obtained from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC), or other tumor types/healthy volunteers in 18 phase I, II, and III trials and analyzed by nonlinear mixed-effects modeling.ResultsA two-compartment model with parallel linear and nonlinear elimination best described the data. During treatment, linear clearance (CL) dominated, resulting in a total CL of 0.173–0.337 L/day, which is similar to other IgG1 monoclonal antibodies. Covariates influencing CL were baseline body weight, aspartate aminotransferase, albumin, gastric cancer, and the presence of liver metastases. MBC and EBC had similar PK parameters, while CL was higher in AGC. Simulations indicated that at least 95% of patients with BC reach concentrations < 1 µg/mL (~ 97% washout) by 7 months. A dose delay in BC or AGC patients of > 1 week would take approximately 6 weeks to get back within steady-state exposure range.ConclusionsTrastuzumab PK for the intravenous formulation was well-described across cancer types, disease status, and regimens. No dose adjustment is required for any of the identified patient covariates. A 7-month serum washout period for trastuzumab is recommended. A reloading dose is required if a maintenance dose is missed by > 1 week.
Highlights
Trastuzumab (Herceptin®; Genentech Inc., South San Francisco, CA, USA), a humanized immunoglobulin G1 (IgG1) monoclonal antibody, binds selectively to the extracellular domain of HER2 with high affinity, resulting in inhibition of downstream signaling pathways, cell cycle arrest, and reduction in angiogenesis [1, 2]
Demographic variables and serum trastuzumab concentration–time data were collected in 18 phase I, II, and III trials to build a comprehensive population pharmacokinetics (PopPK) model for the IV trastuzumab formulation
Nonlinear PK is expected at lower concentrations due to target-mediated drug disposition (TMDD); this was not quantified in the first PopPK model in metastatic breast cancer (MBC) patients as a likely result of the studies in the model, which did not have low trastuzumab concentrations due to qw dosing and insufficient washout periods [3]
Summary
Trastuzumab (Herceptin®; Genentech Inc., South San Francisco, CA, USA), a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb), binds selectively to the extracellular domain of HER2 with high affinity, resulting in inhibition of downstream signaling pathways, cell cycle arrest, and reduction in angiogenesis [1, 2]. It was developed as an intravenous (IV) formulation as a targeted therapy for the management of HER2-positive breast cancer (BC) and became the first FDA-approved biologic for the treatment of solid tumors in 1998 (for HER2-positive metastatic BC [MBC]). These models generally report a total clearance (CL) at steady state of approximately 0.24 L/h and a terminal elimination half-life between 25 and 30 days following the q3w IV regimen in BC
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