Identifying Optimal Biologic Doses of Everolimus (RAD001) in Patients With Cancer Based on the Modeling of Preclinical and Clinical Pharmacokinetic and Pharmacodynamic Data
- 1 April 2008
- journal article
- phase i-and-clinical-pharmacology
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 26 (10), 1596-1602
- https://doi.org/10.1200/jco.2007.14.1127
Abstract
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.Keywords
This publication has 21 references indexed in Scilit:
- 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 TumorsJournal of Clinical Oncology, 2008
- Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With Advanced Solid TumorsJournal of Clinical Oncology, 2008
- Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphomaLeukemia, 2006
- mTOR and cancer therapyOncogene, 2006
- Current development of mTOR inhibitors as anticancer agentsNature Reviews Drug Discovery, 2006
- Biochemical monitoring of mTOR inhibitor-based immunosuppression following kidney transplantation: A novel approach for tailored immunosuppressive therapyKidney International, 2005
- Dual Inhibition of mTOR and Estrogen Receptor SignalingIn vitroInduces Cell Death in Models of Breast CancerClinical Cancer Research, 2005
- The mTOR Inhibitor RAD001 Sensitizes Tumor Cells to DNA-Damaged Induced Apoptosis through Inhibition of p21 TranslationCell, 2005
- Antitumor Efficacy of Intermittent Treatment Schedules with the Rapamycin Derivative RAD001 Correlates with Prolonged Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood Mononuclear CellsCancer Research, 2004
- Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearanceJournal of Pharmacokinetics and Biopharmaceutics, 1977