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

• Published in: Clinical cancer research Vol. 12; no. 2; pp. 536 - 542
• Main Authors: SWEENEY, Christopher J, TAKIMOTO, Chris H, CHAUDHURI, Tuhin, SANDLER, Alan, MITA, Alain C, ROWINSKY, Eric K, LATZ, Jane E, BAKER, Sharyn D, MURRY, Daryl J, KRULL, James H, FIFE, Karen, BATTIATO, Linda, CLEVERLY, Ann, CHAUDHARY, Ajai K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-01-2006
• Subjects: Adult; advanced cancer; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - toxicity; Antineoplastic agents; aspirin; Aspirin - pharmacokinetics; Aspirin - toxicity; Biological and medical sciences; Creatinine - blood; Cross-Over Studies; Drug Interactions; Drug Therapy, Combination; Female; Glutamates - pharmacokinetics; Glutamates - toxicity; Guanine - analogs & derivatives; Guanine - pharmacokinetics; Guanine - toxicity; Humans; ibuprofen; Ibuprofen - pharmacokinetics; Ibuprofen - toxicity; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; NSAIDs; Pemetrexed; Pharmacology. Drug treatments; Thymidylate Synthase - antagonists & inhibitors; Treatment Outcome; Antineoplastic agent; Human; Prostaglandin-endoperoxide synthase; Enzyme; Toxicity; Enzyme inhibitor; Acetylsalicylic acid; Malignant tumor; Pemetrexed; Antiplatelet agent; Antifolate; Ibuprofen; Arylpropionic acid derivatives; Advanced stage; Drug interaction; Oxidoreductases; Salicylates; Pharmacokinetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1834

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/m 2 ) 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 B 12 . Aspirin (325 mg) or ibuprofen (400 mg; 2 × 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/m 2 ) 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).