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ABSTRACT: Purpose
Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM.Patients and methods
A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions.Results
Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate.Conclusion
The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.
SUBMITTER: Hofmeister CC
PROVIDER: S-EPMC3164245 | biostudies-literature | 2011 Sep
REPOSITORIES: biostudies-literature
Hofmeister Craig C CC Yang Xiaoxia X Pichiorri Flavia F Chen Ping P Rozewski Darlene M DM Johnson Amy J AJ Lee Seungsoo S Liu Zhongfa Z Garr Celia L CL Hade Erinn M EM Ji Jia J Schaaf Larry J LJ Benson Don M DM Kraut Eric H EH Hicks William J WJ Chan Kenneth K KK Chen Ching-Shih CS Farag Sherif S SS Grever Michael R MR Byrd John C JC Phelps Mitch A MA
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20110808 25
<h4>Purpose</h4>Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM.<h4>Patients and methods</h4>A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per ...[more]