The AAPS Journal

, Volume 13, Issue 2, pp 230–239

Evaluation of α2-Integrin Expression as a Biomarker for Tumor Growth Inhibition for the Investigational Integrin Inhibitor E7820 in Preclinical and Clinical Studies

  • Ron J. Keizer
  • Y. Funahashi
  • T. Semba
  • J. Wanders
  • J. H. Beijnen
  • J. H. M. Schellens
  • A. D. R. Huitema
Research Article

DOI: 10.1208/s12248-011-9260-2

Cite this article as:
Keizer, R.J., Funahashi, Y., Semba, T. et al. AAPS J (2011) 13: 230. doi:10.1208/s12248-011-9260-2

Abstract

E7820 is an orally active inhibitor of α2-integrin mRNA expression, currently tested in phases I and II. We aimed to evaluate what levels of inhibition of integrin expression are needed to achieve tumor stasis in mice, and to compare this to the level of inhibition achieved in humans. Tumor growth inhibition was measured in mice bearing a pancreatic KP-1 tumor, dosed at 12.5–200 mg/kg over 21 days. In the phase I study, E7820 was administered daily for 28 days over a range of 0–200 mg, followed by a 7-day washout period. PK-PD models were developed in NONMEM. α2-Integrin expression measured on platelets, corresponding to tumor stasis at t = 21 in 50% and 90% of the mice (Iint,50, Iint,90) were calculated. It was evaluated if these levels of inhibition could be achieved in patients at tolerable doses. One hundred nineteen α2-Integrin measurements and 210 tumor size measurements were available from mice. The relationship between PK and α2-integrin expression was modeled using an indirect-effect model, subsequently linked to an exponential tumor growth model. Iinh,50 and Iinh,90 were 14.7% (RSE 7%) and 17.9% (RSE 8%). Four hundred sixty two α2-integrin measurements were available from 29 patients. Using the schedule of 100 mg qd (MTD), α2-integrin expression was inhibited more strongly than the Iint,50 and Iint,90 in greater than 95% and greater than 50% of patients, respectively. Moderate inhibition of α2-integrin expression corresponded to tumor stasis in mice, and similar levels could be reached in patients with the dose level of 100 mg qd.

Key words

biomarkerE7820modeling and simulationoncologypharmacodynamics

Copyright information

© The Author(s) 2011

Authors and Affiliations

  • Ron J. Keizer
    • 1
  • Y. Funahashi
    • 2
  • T. Semba
    • 3
  • J. Wanders
    • 4
  • J. H. Beijnen
    • 1
    • 5
  • J. H. M. Schellens
    • 4
    • 5
  • A. D. R. Huitema
    • 1
  1. 1.Department of Pharmacy and PharmacologyThe Netherlands Cancer Institute/Slotervaart HospitalAmsterdamThe Netherlands
  2. 2.Research Laboratories Eisai Co., Ltd.IbarakiJapan
  3. 3.Eisai Co., LtdHatfieldUK
  4. 4.Division of Clinical Pharmacology, Department of Medical OncologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  5. 5.Division of Drug Toxicology, Section of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of ScienceUtrecht UniversityUtrechtThe Netherlands