Identifying Optimal Biologic Doses of Everolimus (RAD001) in Patients With Cancer Based on the Modeling of Preclinical and Clinical Pharmacokinetic and Pharmacodynamic Data
| Autor: | George Thomas, Terence O'reilly, Chiaki Tanaka, Ian Judson, Anne Boulay, John M. Kovarik, Eric Raymond, Sabine Zumstein-Mecker, Marc Hattenberger, N. Shand, Katharine Hazell, Christine Stephan, Heidi Lane |
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| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Phases of clinical research P70-S6 Kinase 1 Pharmacology Models Biological Peripheral blood mononuclear cell Drug Administration Schedule Pharmacokinetics Neoplasms medicine Animals Humans Everolimus Sirolimus Protein synthesis inhibitor Dose-Response Relationship Drug business.industry Ribosomal Protein S6 Kinases 70-kDa Cancer medicine.disease Rats Pancreatic Neoplasms Oncology Pharmacodynamics business Immunosuppressive Agents medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 26:1596-1602 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2007.14.1127 |
| Popis: | PurposeTo 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 MethodsInhibition 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.ResultsTime- 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.ConclusionA 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. |
| Databáze: | OpenAIRE |
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