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Two Drug Interaction Studies Evaluating the Pharmacokinetics and Toxicity of Pemetrexed When Coadministered with Aspirin or Ibuprofen in Patients with Advanced Cancer

Authors' Affiliations: ¹ Indiana University Cancer Center; ² Eli Lilly and Co., Indianapolis, Indiana; ³ Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas; ⁴ Purdue University, West Lafayette, Indiana; and ⁵ Eli Lilly and Co., Windlesham, Surrey, United Kingdom

Requests for reprints: Eric K. Rowinsky, ImClone Systems, Inc., 33 ImClone Drive, Branchburg, NJ 08876. Phone: 908-203-6912; Fax: 908-231-9885; E-mail: erowinsky{at}oncodrugs.com.

Purpose: Pemetrexed is an antimetabolite that is structurally similar to methotrexate. Because nonsteroidal anti-inflammatory drugs (NSAID) impair methotrexate clearance and increase its toxicity, we evaluated the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or ibuprofen in advanced cancer patients.

Experimental Design: In two independent, randomized, crossover drug interaction studies, cancer patients with a creatinine clearance (CrCl) 60 mL/min received an NSAID (aspirin or ibuprofen) with either the first or the second dose of pemetrexed (cycle 1 or 2). Pemetrexed (500 mg/m²) was infused i.v. on day 1 of a 21-day cycle, and all patients were supplemented with oral folic acid and i.m. vitamin B₁₂. Aspirin (325 mg) or ibuprofen (400 mg; 2 x 200 mg) was given orally every 6 hours, starting 2 days before pemetrexed administration, with the ninth and final dose taken 1 hour before infusion. Pemetrexed pharmacokinetics with and without concomitant NSAID treatment were compared for cycles 1 and 2.

Results: Data from 27 patients in each study were evaluable for the analysis of pemetrexed pharmacokinetics. Coadministration of aspirin did not alter pemetrexed pharmacokinetics; however, ibuprofen coadministration was associated with a 16% reduction in clearance, a 15% increase in maximum plasma concentration, and a 20% increase in area under the plasma concentration versus time curve but no significant change in V_ss compared with pemetrexed alone. No febrile neutropenia occurred in any patient, and no increase in pemetrexed-related toxicity was associated with NSAID administration.

Conclusions: Pemetrexed (500 mg/m²) with vitamin supplementation is well tolerated and requires no dosage adjustment when coadministered with aspirin (in patients with CrCl 60 mL/min) or ibuprofen (in patients with CrCl 80 mL/min).

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