title: Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Hofmeister
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.forename: Flavia
authors.initials: F
authors.lastname: Pichiorri
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Darlene M
authors.initials: DM
authors.lastname: Rozewski
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Seungsoo
authors.initials: S
authors.lastname: Lee
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Liu
authors.forename: Celia L
authors.initials: CL
authors.lastname: Garr
authors.forename: Erinn M
authors.initials: EM
authors.lastname: Hade
authors.forename: Jia
authors.initials: J
authors.lastname: Ji
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Schaaf
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
authors.forename: Eric H
authors.initials: EH
authors.lastname: Kraut
authors.forename: William J
authors.initials: WJ
authors.lastname: Hicks
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Sherif S
authors.initials: SS
authors.lastname: Farag
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015153:Blotting, Western; D004347:Drug Interactions; D006801:Humans; D000077269:Lenalidomide; D020714:Maximum Tolerated Dose; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D013792:Thalidomide; C401859:temsirolimus; D000077269:Lenalidomide; D020123:Sirolimus