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- Title
Population pharmacokinetics and exposure-response analyses of trastuzumab in patients with advanced gastric or gastroesophageal junction cancer.
- Authors
Cosson, Valérie; Ng, Vivian; Lehle, Michaela; Lum, Bert
- Abstract
Purpose: The aim of this study was to characterize trastuzumab population pharmacokinetics (PKs) in patients with human epidermal growth factor receptor 2-positive advanced gastric or gastroesophageal junction cancer and the relationship of trastuzumab PK with patient response. Methods: A nonlinear mixed effects PK model was built using data from the ToGA study. Patients were randomized to intravenous trastuzumab plus chemotherapy or chemotherapy alone. The influence of demographic, laboratory, and disease characteristics on PK parameters was assessed. An exploratory exposure-response analysis compared various PK parameters at steady state with best overall tumor response and overall survival (OS). Results: Trastuzumab PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. Total clearance (and half-life) of trastuzumab was concentration-dependent. Body weight, prior gastrectomy, and serum albumin had the greatest influence on trastuzumab PK; increasing weight and decreasing albumin levels were associated with increased clearance, while prior gastrectomy correlated with decreased clearance. Median values for AUC, C, and C were lower in patients with progressive disease (PD) than other response categories, although the 1.5 interquartile ranges overlapped. Patients with the lowest C had the highest PD rate and a shorter OS. Conclusions: In the advanced gastric cancer population, trastuzumab PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Predicted PK exposure was lower than previously reported for breast cancer. Patients with the lowest C had a shorter OS and the highest PD rate, but a distinct correlation was not observed for tumor response.
- Subjects
STOMACH cancer patients; PHARMACOKINETICS; TRASTUZUMAB; STOMACH cancer treatment; EPIDERMAL growth factor receptors; ESOPHAGOGASTRIC junction cancer; CANCER chemotherapy; THERAPEUTICS
- Publication
Cancer Chemotherapy & Pharmacology, 2014, Vol 73, Issue 4, p737
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-014-2400-5