Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 4, pp 819–829

Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors

Authors

  • Amit Garg
    • Clinical Pharmacology, MS 463aGenentech, Inc.
    • Clinical Pharmacology, MS 463aGenentech, Inc.
  • Jing Li
    • Clinical Pharmacology, MS 463aGenentech, Inc.
    • MedImmune
  • Jin Jin
    • Clinical Pharmacology, MS 463aGenentech, Inc.
  • D. Russell Wada
    • Quantitative Solutions Inc.
  • Hanbin Li
    • Quantitative Solutions Inc.
  • Javier Cortés
    • Department of OncologyVall d’Hebron University Hospital
  • Virginia McNally
    • F. Hoffmann-La Roche Ltd
  • Graham Ross
    • F. Hoffmann-La Roche Ltd
  • Jennifer Visich
    • Clinical Pharmacology, MS 463aGenentech, Inc.
  • Bert Lum
    • Clinical Pharmacology, MS 463aGenentech, Inc.
Original Article

DOI: 10.1007/s00280-014-2560-3

Cite this article as:
Garg, A., Quartino, A., Li, J. et al. Cancer Chemother Pharmacol (2014) 74: 819. doi:10.1007/s00280-014-2560-3

Abstract

Purpose

To characterize the population pharmacokinetics (PK) of pertuzumab across clinical trials in a variety of solid tumors, evaluate the potential impact of patient characteristics on PK, and confirm the appropriateness of the fixed (non-weight-based) dose.

Methods

Pertuzumab concentration data collected following intravenous administration during eleven phase I/II studies and the pivotal phase III trial CLEOPATRA were analyzed using nonlinear mixed-effects modeling. The potential impact of patient and laboratory characteristics and HER2 target-related variables on pertuzumab PK were investigated in a covariate analysis. The final model was used to confirm selection of fixed, non-weight-based dosing of pertuzumab, and to compare pertuzumab PK in CLEOPATRA with the other studies.

Results

The analysis included 4,525 serum concentration measurements from 481 patients with solid tumors. Pertuzumab PK in the 2–25 mg/kg dose range was described by a two-compartment linear model with first-order elimination. The elimination clearance and central compartment volume were 0.235 L/day, and 3.11 L, respectively, and the terminal elimination half-life was 18.0 days. Baseline serum albumin and lean body weight had statistically significant effects on pertuzumab clearance; however, simulations showed that the magnitude of their effects on pertuzumab exposure was minimal compared with overall variability and was not clinically relevant. Thus, variations in these factors do not require dose adjustments.

Conclusions

The fixed, non-weight-based dosing of pertuzumab, 840 mg loading dose followed by a 420 mg maintenance dose every 3 weeks, in patients with the solid tumors in this analysis is well supported by the population pharmacokinetic modeling and simulation results.

Keywords

Fixed doseHER2PertuzumabPopulation pharmacokinetics modelingMetastatic breast cancerNONMEM

Supplementary material

280_2014_2560_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 22 kb)
280_2014_2560_MOESM2_ESM.pdf (107 kb)
Pertuzumab two-compartment model with first-order rate elimination (k10 elimination rate constant, k12 rate constant from central to peripheral compartment, k21 rate constant from peripheral to central compartment, CL elimination clearance, Q distribution clearance, R0 drug infusion rate, Vc volume of central compartment, Vp peripheral volume) (PDF 107 kb)
280_2014_2560_MOESM3_ESM.pdf (1.9 mb)
Goodness-of-fit plots of final model showing: individual observed versus predicted concentrations plotted on a log (A) or linear scale (B); conditional weighted residuals (CWRES) versus time (C); population observed versus predicted concentrations plotted on a log (D) or linear scale (E); CWRES versus. population predicted concentrations (F) (PDF 1936 kb)
280_2014_2560_MOESM4_ESM.pdf (1.1 mb)
Observed effects of CRP (A), HER2 ECD (B), and HER2 expression level (C) on pertuzumab PK parameters. (A) Circles represent individual parameter estimates (normalized for LBW of 48 kg and ALBU of 3.9 g/dL), the solid line represents the modeled covariate relationship, and the dotted line is a smooth local regression curve (LOWESS). (B) Circles represent individual parameter estimates (normalized for LBW of 48 kg and ALBU of 3.9 g/dL), the solid line represents the modeled covariate relationship, and the dotted line is a smooth local regression curve (LOESS). (C) Circles represent the individual parameter estimates (normalized for LBW of 48 kg and ALBU of 3.9 g/dL), the solid lines are the modeled PK parameters, and the gray bars represent the median PK parameter values (PDF 1104 kb)
280_2014_2560_MOESM5_ESM.pdf (379 kb)
The impact of baseline body weight on simulated pertuzumab steady-state model-predicted trough concentrations (Cmin,SS) (PDF 378 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014