Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 4, pp 737–747 | Cite as

Population pharmacokinetics and exposure–response analyses of trastuzumab in patients with advanced gastric or gastroesophageal junction cancer

  • Valérie F. Cosson
  • Vivian W. Ng
  • Michaela Lehle
  • Bert L. Lum
Original Article

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, Cmax, and Cmin were lower in patients with progressive disease (PD) than other response categories, although the 1.5 interquartile ranges overlapped. Patients with the lowest Cmin 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 Cmin had a shorter OS and the highest PD rate, but a distinct correlation was not observed for tumor response.

Keywords

Trastuzumab Gastric cancer Gastroesophageal junction cancer Population pharmacokinetics Exposure–response 

Notes

Acknowledgments

The study was funded by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this manuscript was provided by Genentech, Inc.

Conflict of interest

Valérie F. Cosson and Michaela Lehle are employed by F. Hoffman-La Roche Ltd. Vivian W. Ng and Bert L. Lum are employed by Genentech, Inc., a member of the Roche group.

Supplementary material

280_2014_2400_MOESM1_ESM.docx (699 kb)
Supplementary material 1 (DOCX 698 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Valérie F. Cosson
    • 1
  • Vivian W. Ng
    • 2
  • Michaela Lehle
    • 1
  • Bert L. Lum
    • 2
  1. 1.F. Hoffmann-La Roche Ltd.BaselSwitzerland
  2. 2.Genentech Inc.South San FranciscoUSA

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