PMID- 18332467 OWN - NLM STAT- MEDLINE DCOM- 20080617 LR - 20220409 IS - 1527-7755 (Electronic) IS - 0732-183X (Linking) VI - 26 IP - 10 DP - 2008 Apr 1 TI - Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. PG - 1596-602 LID - 10.1200/JCO.2007.14.1127 [doi] AB - 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. FAU - Tanaka, Chiaki AU - Tanaka C AD - Novartis Pharmaceuticals Corp, East Hanover, NJ, USA. FAU - O'Reilly, Terence AU - O'Reilly T FAU - Kovarik, John M AU - Kovarik JM FAU - Shand, Nicholas AU - Shand N FAU - Hazell, Katharine AU - Hazell K FAU - Judson, Ian AU - Judson I FAU - Raymond, Eric AU - Raymond E FAU - Zumstein-Mecker, Sabine AU - Zumstein-Mecker S FAU - Stephan, Christine AU - Stephan C FAU - Boulay, Anne AU - Boulay A FAU - Hattenberger, Marc AU - Hattenberger M FAU - Thomas, George AU - Thomas G FAU - Lane, Heidi A AU - Lane HA LA - eng GR - DK73802/DK/NIDDK NIH HHS/United States GR - U01 CA84292-06/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20080310 PL - United States TA - J Clin Oncol JT - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JID - 8309333 RN - 0 (Immunosuppressive Agents) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Everolimus MH - Humans MH - Immunosuppressive Agents/*administration & dosage MH - Models, Biological MH - Neoplasms/*drug therapy MH - Pancreatic Neoplasms/drug therapy/metabolism MH - Rats MH - Ribosomal Protein S6 Kinases, 70-kDa/*antagonists & inhibitors MH - Sirolimus/administration & dosage/*analogs & derivatives/pharmacokinetics/pharmacology EDAT- 2008/03/12 09:00 MHDA- 2008/06/18 09:00 CRDT- 2008/03/12 09:00 PHST- 2008/03/12 09:00 [pubmed] PHST- 2008/06/18 09:00 [medline] PHST- 2008/03/12 09:00 [entrez] AID - JCO.2007.14.1127 [pii] AID - 10.1200/JCO.2007.14.1127 [doi] PST - ppublish SO - J Clin Oncol. 2008 Apr 1;26(10):1596-602. doi: 10.1200/JCO.2007.14.1127. Epub 2008 Mar 10.