NDLI: Evaluation of α$_{2}$-Integrin Expression as a Biomarker for Tumor Growth Inhibition for the Investigational Integrin Inhibitor E7820 in Preclinical and Clinical Studies

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Evaluation of α$_{2}$-Integrin Expression as a Biomarker for Tumor Growth Inhibition for the Investigational Integrin Inhibitor E7820 in Preclinical and Clinical Studies

Content Provider	Springer Nature Link
Author	Keizer, Ron J. Funahashi, Y. Semba, T. Wanders, J. Beijnen, J. H. Schellens, J. H. M. Huitema, A. D. R.
Copyright Year	2011
Abstract	E7820 is an orally active inhibitor of α$_{2}$-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. α$_{2}$-Integrin expression measured on platelets, corresponding to tumor stasis at t = 21 in 50% and 90% of the mice (I $_{int,50}$, I $_{int,90}$) were calculated. It was evaluated if these levels of inhibition could be achieved in patients at tolerable doses. One hundred nineteen α$_{2}$-Integrin measurements and 210 tumor size measurements were available from mice. The relationship between PK and α$_{2}$-integrin expression was modeled using an indirect-effect model, subsequently linked to an exponential tumor growth model. I $_{inh,50}$ and I $_{inh,90}$ were 14.7% (RSE 7%) and 17.9% (RSE 8%). Four hundred sixty two α$_{2}$-integrin measurements were available from 29 patients. Using the schedule of 100 mg qd (MTD), α$_{2}$-integrin expression was inhibited more strongly than the I $_{int,50}$ and I $_{int,90}$ in greater than 95% and greater than 50% of patients, respectively. Moderate inhibition of α$_{2}$-integrin expression corresponded to tumor stasis in mice, and similar levels could be reached in patients with the dose level of 100 mg qd.
Starting Page	230
Ending Page	239
Page Count	10
File Format	PDF
ISSN	12341234
Journal	The AAPS Journal
Volume Number	13
Issue Number	2
e-ISSN	15507416
Language	English
Publisher	Springer US
Publisher Date	2011-03-09
Publisher Institution	American Association of Pharmaceutical Scientists
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	biomarker E7820 modeling and simulation oncology pharmacodynamics Pharmacy Biotechnology Biochemistry Pharmacology/Toxicology
Content Type	Text
Resource Type	Article

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