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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

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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.

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Acknowledgments

The study was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland, and Genentech, Inc., a member of the Roche Group, South San Francisco, CA, USA. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd. The authors also acknowledge the contributions of the clinical pharmacologists Michael Brewster and David Allison in the conduct of many of the studies included in this analysis, Ihsan Nijem for bioanalytical support, and Shweta Vadhavkar and Kristie Kooken for statistical programming support. The authors would also like to thank all participating patients and their families.

Author information

Author notes

  1. Jing Li

    Present address: MedImmune, 24500 Clawiter Road, Hayward, CA, 94545, USA

Authors and Affiliations

  1. Clinical Pharmacology, MS 463a, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Amit Garg, Angelica Quartino, Jing Li, Jin Jin, Jennifer Visich & Bert Lum

  2. Quantitative Solutions Inc., Menlo Park, CA, 94025, USA

    D. Russell Wada & Hanbin Li

  3. Department of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

    Javier Cortés

  4. F. Hoffmann-La Roche Ltd, 6 Falcon Way, Shire Park, Hexagon Place, Welwyn Garden City, AL7 1TW, Hertfordshire, UK

    Virginia McNally & Graham Ross

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  1. Amit Garg
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Correspondence to Angelica Quartino.

Electronic supplementary material

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Supplementary material 1 (DOCX 22 kb)

280_2014_2560_MOESM2_ESM.pdf

Pertuzumab two-compartment model with first-order rate elimination (k 10 elimination rate constant, k 12 rate constant from central to peripheral compartment, k 21 rate constant from peripheral to central compartment, CL elimination clearance, Q distribution clearance, R 0 drug infusion rate, Vc volume of central compartment, Vp peripheral volume) (PDF 107 kb)

280_2014_2560_MOESM3_ESM.pdf

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

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

The impact of baseline body weight on simulated pertuzumab steady-state model-predicted trough concentrations (Cmin,SS) (PDF 378 kb)

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Garg, A., Quartino, A., Li, J. et al. 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. Cancer Chemother Pharmacol 74, 819–829 (2014). https://doi.org/10.1007/s00280-014-2560-3

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  • DOI: https://doi.org/10.1007/s00280-014-2560-3

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