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1¡¢Preclinical pharmacokinetic/pharmacodynamic models of gefitinib and the design of equivalent dosing regimens in EGFR wild-type and mutant tumor models.
2¡¢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.
3¡¢this study was to evaluate if the hormonal therapy with BCLT can affect the EGFR-targeted therapy using primary cultures obtained from 22 human PCa tissues harvested after radical prostatectomy (RP) in patients who received (n=10) BCLT and those that did not (n=12) as neoadjuvant hormone therapy (NHT).
We demonstrated that cultures derived from PCa tissues harvested after NHT presented significantly higher EGFR and Her2 levels compared to cultures derived from control patients. However, cultures derived from patients with NHT were less sensitive to gefitinib when compared to cultures derived from control patients. Conversely, BCLT effectiveness did not seem to be different in the two groups and was partially additive with gefitinib in the NHT group and additive/synergistic in the control group. Cultures (8/22) were negative for the expression of the PTEN gene and we observed no differences in the two groups. Thus the different IC50 values observed for gefitinib and the partial additivity in the combination treatment with gefitinib and BCLT is influenced by EGFR/Her2 ratio because it was shown that EGFR inhibition was lower when Her2 is overexpressed.
Taken together, our results indicate that anti-EGFR targeted therapies and a possible combination therapy involving gefitinib and BCLT should be performed early in naive patients when Her2 is not overexpressed and before the anti-androgenic hormone therapy induces such an undesirable effect.
4¡¢Cancer Chemother Pharmacol. 2012 Jan;69(1):273-80. Epub 2011 Oct 15.
5¡¢Center for Applied Molecular Medicine, University of Southern California Westside
Cancer Center, Beverly Hills, CA, USA.
6¡¢PMID:22002543[PubMed - indexed for MEDLINE]
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