Clinical Development of MET Targeted Therapy For Human Cancer

Tirgan, Nima; Tang, Zhe; Chi-Chung, Patrick

doi:10.2174/157339409789712708

Cited by 1 publication

(1 citation statement)

References 75 publications

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“…This suggests a multitargeted approach may be better for certain cancer therapies including overcoming acquired treatment resistance. It is noteworthy that some clinical MET inhibitor candidates are considered to be highly selective, whereas others are multitargeted inhibitors (Faoro et al, 2009;Tirgan et al, 2009). It remains to be seen whether highly selective MET inhibitors or multitargeted inhibitors (or a combination of selective MET inhibitor with other tyrosine kinase inhibitors) will provide a better success in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Modeling of Crizotinib for Anaplastic Lymphoma Kinase Inhibition and Antitumor Efficacy in Human Tumor Xenograft Mouse Models

Yamazaki¹,

Vicini²,

Shen³

et al. 2011

J Pharmacol Exp Ther

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Crizotinib [Xalkori; PF02341066; (R)-3-[1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine] is an orally available dual inhibitor of anaplastic lymphoma kinase (ALK) and hepatocyte growth factor receptor. The objectives of the present studies were to characterize: 1) the pharmacokinetic/pharmacodynamic relationship of crizotinib plasma concentrations to the inhibition of ALK phosphorylation in tumors, and 2) the relationship of ALK inhibition to antitumor efficacy in human tumor xenograft models. Crizotinib was orally administered to athymic nu/nu mice implanted with H3122 nonsmall-cell lung carcinomas or severe combined immunodeficient/ beige mice implanted with Karpas299 anaplastic large-cell lymphomas. Plasma concentration-time courses of crizotinib were adequately described by a one-compartment pharmacokinetic model. A pharmacodynamic link model reasonably fit the time courses of ALK inhibition in both H3122 and Karpas299 models with EC 50 values of 233 and 666 ng/ml, respectively. A tumor growth inhibition model also reasonably fit the time course of individual tumor growth curves with EC 50 values of 255 and 875 ng/ml, respectively. Thus, the EC 50 for ALK inhibition approximately corresponded to the EC 50 for tumor growth inhibition in both xenograft models, suggesting that Ͼ50% ALK inhibition would be required for significant antitumor efficacy (Ͼ50%). Furthermore, based on the observed clinical pharmacokinetic data coupled with the pharmacodynamic parameters obtained from the present nonclinical xenograft mouse model, Ͼ70% ALK inhibition was projected in patients with non-small-cell lung cancer who were administered the clinically recommended dosage of crizotinib, twice-daily doses of 250 mg (500 mg/day). The result suggests that crizotinib could sufficiently inhibit ALK phosphorylation for significant antitumor efficacy in patients.

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Section: Discussionmentioning

confidence: 99%