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Research Articles: Therapeutics, Targets, and Development

Preclinical pharmacokinetic/pharmacodynamic models of gefitinib and the design of equivalent dosing regimens in EGFR wild-type and mutant tumor models

Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, Pennsylvania

Requests for reprints: James M. Gallo, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140. Phone: 215-707-9699; Fax: 215-707-9409. E-mail: jmgallo{at}temple.edu

Abstract

Epidermal growth factor receptor (EGFR) inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic (PG) dimension to any pharmacokinetic (PK) and pharmacodynamic (PD) analysis. The goal of this investigation was to cast the combined PG/PK/PD variables into models that could be used to design equivalent PK/PD dosing regimens for gefitinib in genetically distinct tumor models. To this end, groups of mice bearing either s.c. LN229-wild-type EGFR or LN229-EGFRvIII mutant tumors, an EGFR inhibitor-sensitizing mutation, were given gefitinib at doses of 10 mg/kg i.v., 50 mg/kg intraarterially, and 150 mg/kg p.o. In each group, gefitinib plasma and tumor concentrations were quantitated, as were tumoral amounts of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (pERK), a PD end point that was shown to respond in a dose-dependent manner in each tumor type. Hybrid physiologically based PK/PD models were developed for each tumor type, which consisted of a forcing function describing the plasma drug concentration profile, a tumor compartment depicting drug disposition in tumor, and a mechanistic target-response PD model characterizing pERK in the tumor. Gefitinib showed analogous PK properties in each tumor type yet different PD characteristics consistent with the EGFR status of the tumors. Using the PK/PD model for each tumor type, simulations were done to define multiple-dose regimens for gefitinib that yielded equivalent PD profiles of pERK in each tumor type. The novel concept of PK/PD equivalent dosing regimens could be applied in drug development and to delineate PG differences in drug activity. [Mol Cancer Ther 2008;7(2):407–17]

Grant support: NIH grants CA72937 and CA85577 (J.M. Gallo).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 9/12/08; revised 11/ 6/07; accepted 12/28/07.