Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein.
Abstract | PURPOSE: 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:
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Authors | Craig C Hofmeister, Xiaoxia Yang, Flavia Pichiorri, Ping Chen, Darlene M Rozewski, Amy J Johnson, Seungsoo Lee, Zhongfa Liu, Celia L Garr, Erinn M Hade, Jia Ji, Larry J Schaaf, Don M Benson Jr, Eric H Kraut, William J Hicks, Kenneth K Chan, Ching-Shih Chen, Sherif S Farag, Michael R Grever, John C Byrd, Mitch A Phelps |
Journal | Journal of clinical oncology : official journal of the American Society of Clinical Oncology
(J Clin Oncol)
Vol. 29
Issue 25
Pg. 3427-34
(Sep 01 2011)
ISSN: 1527-7755 [Electronic] United States |
PMID | 21825263
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- ABCB1 protein, human
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Thalidomide
- temsirolimus
- Lenalidomide
- Sirolimus
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Topics |
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(metabolism)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacokinetics, therapeutic use)
- Blotting, Western
- Drug Interactions
- Humans
- Lenalidomide
- Maximum Tolerated Dose
- Multiple Myeloma
(drug therapy, metabolism)
- Neoplasm Recurrence, Local
(drug therapy, metabolism)
- Sirolimus
(administration & dosage, analogs & derivatives)
- Survival Rate
- Thalidomide
(administration & dosage, analogs & derivatives)
- Tissue Distribution
- Treatment Outcome
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