Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts.

Autor:	Tate SC; Authors' Affiliations: Eli Lilly and Company, Windlesham, United Kingdom; and tate_sonya@network.lilly.com., Cai S; Eli Lilly and Company, Indianapolis, Indiana., Ajamie RT; Eli Lilly and Company, Indianapolis, Indiana., Burke T; Eli Lilly and Company, Indianapolis, Indiana., Beckmann RP; Eli Lilly and Company, Indianapolis, Indiana., Chan EM; Eli Lilly and Company, Indianapolis, Indiana., De Dios A; Eli Lilly and Company, Indianapolis, Indiana., Wishart GN; Authors' Affiliations: Eli Lilly and Company, Windlesham, United Kingdom; and., Gelbert LM; Eli Lilly and Company, Indianapolis, Indiana., Cronier DM; Authors' Affiliations: Eli Lilly and Company, Windlesham, United Kingdom; and.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2014 Jul 15; Vol. 20 (14), pp. 3763-74. Date of Electronic Publication: 2014 May 21.
DOI:	10.1158/1078-0432.CCR-13-2846
Abstrakt:	Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell-cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α, and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by: (i) relating the rate of tumor growth to mitotic cell density, and (ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated antitumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the quantitative pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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