Originally published as JCO Early Release 10.1200/JCO.2007.14.1127 on March 10 2008

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Identifying Optimal Biologic Doses of Everolimus (RAD001) in Patients With Cancer Based on the Modeling of Preclinical and Clinical Pharmacokinetic and Pharmacodynamic Data

Chiaki Tanaka, Terence O’Reilly, John M. Kovarik, Nicholas Shand, Katharine Hazell, Ian Judson, Eric Raymond, Sabine Zumstein-Mecker, Christine Stephan, Anne Boulay, Marc Hattenberger, George Thomas, Heidi A. Lane

From the Novartis Pharmaceuticals Corp, East Hanover, NJ; Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Institute of Cancer Research, Sutton, Surrey, United Kingdom; Hôpital Beaujon, Clichy Cedex, France; and the Genome Research Institute, University of Cincinnati, Cincinnati, OH

Corresponding author: Heidi A. Lane, PhD, Basilea Pharmaceutica Ltd, Grenzacherstrasse 487, PO Box, Basel, Switzerland CH-4005; e-mail: heidi.lane@basilea.com

Purpose: To use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal clinical regimens of everolimus, a novel oral mammalian target of rapamycin (mTOR) inhibitor, to carry forward to expanded phase I with tumor biopsy studies in cancer patients.

Patients and Methods: Inhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship between everolimus concentrations and S6K1 inhibition in PBMCs of cancer patients and in PBMCs and tumors of everolimus-treated CA20948 pancreatic tumor-bearing rats.

Results: Time- and dose-dependent S6K1 inhibition was demonstrated in human PBMCs. In the rat model, a relationship was shown between S6K1 inhibition in tumors or PBMCs and antitumor effect. This allowed development of a direct-link PK/PD model that predicted PBMC S6K1 inhibition-time profiles in patients. Comparison of rat and human profiles simulated by the model suggested that a weekly 20- to 30-mg dose of everolimus would be associated with an antitumor effect in an everolimus-sensitive tumor and that daily administration would exert a greater effect than weekly administration at higher doses.

Conclusion: A direct-link PK/PD model predicting the time course of S6K1 inhibition during weekly and daily everolimus administration allowed extrapolation from preclinical studies and first clinical results to select optimal doses and regimens of everolimus to explore in future clinical trials.

published online ahead of print at www.jco.org on March 10, 2008.

Supported by the National Institutes of Health Mouse Models for Human Cancer Consortium, Grants No. UO1 CA84292-06 and DK73802, and by the Strauss Chair in Cancer Research, University of Cincinnati Medical School (G.T.).

C.T. and T.O. contributed equally to this work.

Presented in part in abstract format at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31 to June 3, 2003.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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