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

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanaka, C. Articles by Lane, H. A. Search for Related Content PubMed PubMed Citation Articles by Tanaka, C. Articles by Lane, H. A. Related Articles Related Articles Related Editorial Social Bookmarking                            What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Articles

• Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With Advanced Solid Tumors
  Anne O'Donnell, Sandrine Faivre, Howard A. Burris, III, Daniel Rea, Vassiliki Papadimitrakopoulou, Nicholas Shand, Heidi A. Lane, Katharine Hazell, Ulrike Zoellner, John M. Kovarik, Cathryn Brock, Suzanne Jones, Eric Raymond, and Ian Judson
  JCO 2008 26: 1588-1595 [Abstract] [Full Text]
• Dose- and Schedule-Dependent Inhibition of the Mammalian Target of Rapamycin Pathway With Everolimus: A Phase I Tumor Pharmacodynamic Study in Patients With Advanced Solid Tumors
  Josep Tabernero, Federico Rojo, Emiliano Calvo, Howard Burris, Ian Judson, Katharine Hazell, Erika Martinelli, Santiago Ramon y Cajal, Suzanne Jones, Laura Vidal, Nicholas Shand, Teresa Macarulla, Francisco Javier Ramos, Sasa Dimitrijevic, Ulrike Zoellner, Pui Tang, Michael Stumm, Heidi A. Lane, David Lebwohl, and José Baselga
  JCO 2008 26: 1603-1610 [Abstract] [Full Text]

Related Editorial

• Dose Selection in Phase I Studies: Why We Should Always Go for the Top
  Stefan Sleijfer and Erik Wiemer
  JCO 2008 26: 1576-1578 [Full Text]

This article has been cited by other articles:

				T. B. Dorff, A. Goldkorn, and D. I. Quinn Review: Targeted therapy in renal cancer Therapeutic Advances in Medical Oncology, November 1, 2009; 1(3): 183 - 205. [Abstract] [PDF]

				I. Okamoto, T. Doi, A. Ohtsu, M. Miyazaki, A. Tsuya, K. Kurei, K. Kobayashi, and K. Nakagawa Phase I Clinical and Pharmacokinetic Study of RAD001 (Everolimus) Administered Daily to Japanese Patients with Advanced Solid Tumors Jpn. J. Clin. Oncol., September 25, 2009; (2009) hyp120v1. [Abstract] [Full Text] [PDF]

				S. L. Ellard, M. Clemons, K. A. Gelmon, B. Norris, H. Kennecke, S. Chia, K. Pritchard, A. Eisen, T. Vandenberg, M. Taylor, et al. Randomized Phase II Study Comparing Two Schedules of Everolimus in Patients With Recurrent/Metastatic Breast Cancer: NCIC Clinical Trials Group IND.163 J. Clin. Oncol., September 20, 2009; 27(27): 4536 - 4541. [Abstract] [Full Text] [PDF]

				J. Baselga, V. Semiglazov, P. van Dam, A. Manikhas, M. Bellet, J. Mayordomo, M. Campone, E. Kubista, R. Greil, G. Bianchi, et al. Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor-Positive Breast Cancer J. Clin. Oncol., June 1, 2009; 27(16): 2630 - 2637. [Abstract] [Full Text] [PDF]

				F. Meric-Bernstam and A. M. Gonzalez-Angulo Targeting the mTOR Signaling Network for Cancer Therapy J. Clin. Oncol., May 1, 2009; 27(13): 2278 - 2287. [Abstract] [Full Text] [PDF]

				H. Wong, M. Belvin, S. Herter, K. P. Hoeflich, L. J. Murray, L. Wong, and E. F. Choo Pharmacodynamics of 2-{4-[(1E)-1-(Hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl}ethan-1-ol (GDC-0879), a Potent and Selective B-Raf Kinase Inhibitor: Understanding Relationships between Systemic Concentrations, Phosphorylated Mitogen-Activated Protein Kinase Kinase 1 Inhibition, and Efficacy J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 360 - 367. [Abstract] [Full Text] [PDF]

				B. M. Wolpin, A. F. Hezel, T. Abrams, L. S. Blaszkowsky, J. A. Meyerhardt, J. A. Chan, P. C. Enzinger, B. Allen, J. W. Clark, D. P. Ryan, et al. Oral mTOR Inhibitor Everolimus in Patients With Gemcitabine-Refractory Metastatic Pancreatic Cancer J. Clin. Oncol., January 10, 2009; 27(2): 193 - 198. [Abstract] [Full Text] [PDF]

				I. E. Haines Dose Selection in Phase I Studies: Why We Should Always Go for the Most Effective J. Clin. Oncol., July 20, 2008; 26(21): 3650 - 3652. [Full Text] [PDF]

				S. Sleijfer and E. Wiemer Dose Selection in Phase I Studies: Why We Should Always Go for the Top J. Clin. Oncol., April 1, 2008; 26(10): 1576 - 1578. [Full Text] [PDF]