Effect of Aspirin and Sulindac on Methotrexate Clearance

Fürst, Daniel E.; Herman, Ronald A.; Koehnke, R; Ericksen, Nils; Hash, Linda; Riggs, Charles E.; Porras, Arturo G.; Veng‐Pedersen, Peter

doi:10.1002/jps.2600790907

Cited by 72 publications

(35 citation statements)

References 22 publications

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“…Several studies of methotrexate have documented decreases in total systemic clearance and corresponding increases in AUC with coadministration of salicylates (11,19,20); however, all of the positive methotrexate-aspirin drug interaction studies used higher doses of aspirin than our current clinical trial. Other studies evaluating the effects of ibuprofen on methotrexate kinetics have provided inconsistent results and thus offer little context for interpreting the influence of ibuprofen on pemetrexed clearance (22,23).…”

Section: Discussionmentioning

confidence: 77%

“…The dose of aspirin used in this study (equivalent to 1.3 g/d) mimics the most common analgesic regimens and far exceeds that used for the prevention of myocardial infarction; however, higher doses of aspirin (2.5-3.9 g/d) are sometimes used to treat diseases, such as rheumatoid arthritis. These high-dose regimens can produce plasma salicylate levels of f200 Ag/mL and have been shown to alter methotrexate clearance (19,20). Because this interaction may be salicylate concentration dependent, the possibility that higher aspirin doses could alter pemetrexed pharmacokinetics cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

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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

Sweeney

Takimoto

Latz

et al. 2006

Clinical Cancer Research

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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) z60 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 Â 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 1and 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 z60 mL/min) or ibuprofen (in patients with CrCl z80 mL/min).Pemetrexed is a novel antifolate that inhibits three folatedependent enzymes involved in purine and pyrimidine synthesis: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase (1). In preclinical studies, pemetrexed was effective against some methotrexateresistant cell lines (1, 2), suggesting that its mechanism of action may differ from that of classic antifolates. The drug has shown antitumor activity in a range of solid malignancies, including mesothelioma, non -small cell lung, bladder, head and neck, breast, cervical, colorectal, pancreatic, and gastric cancers (3, 4). Pemetrexed has received regulatory approval for the treatment of malignant pleural mesothelioma in combination with cisplatin and as single-agent therapy for second-line treatment of non -small cell lung cancer (5 -7).Pharmacokinetic evaluations for three phase I dose-escalation trials showed that pemetrexed is f80% protein bound, with rapid plasma distribution and elimination phases, and exhibits linear pharmacokinetics over a broad range of doses (0.2-838 mg/m 2 ). The steady-state volume of distribution (V ss ) of pemetrexed is small (16 L), suggesti...

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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

Sweeney

Takimoto

Latz

et al. 2006

Clinical Cancer Research

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“…For ibuprofen and naproxen, studies showed conflicting results [33][34][35] . Four studies evaluating high-dose ASA (1.3-4.5 g/day) reported an increase of serum concentration of MTX [45][46][47][48] (Level of evidence 4).…”

Section: Resultsmentioning

confidence: 99%

Canadian Recommendations for Use of Methotrexate in Patients with Rheumatoid Arthritis

Katchamart¹,

Bourré‐Tessier²,

Donka³

et al. 2010

J Rheumatol

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Objective.To develop recommendations for the use of methotrexate (MTX) in patients with rheumatoid arthritis.Methods.Canadian rheumatologists who participated in the international 3e Initiative in Rheumatology (evidence, expertise, exchange) in 2007–2008 formulated 5 unique Canadian questions. A bibliographic team systematically reviewed the relevant literature on these 5 topics. An expert committee consisting of 26 rheumatologists from across Canada was convened, and a set of recommendations was proposed based on the results of systematic reviews combined with expert opinions using a nominal group consensus process.Results.The 5 questions addressed drug interactions, predictors of response, strategies to reduce non-serious side effects, variables to assess clinical response, and incorporating patient preference into decision-making. The systematic review retrieved 93 pertinent articles; this evidence was presented to the expert committee during the interactive workshop. After extensive discussion and voting, a total of 9 recommendations were formulated: 2 on drug interactions, 1 on predictors of response, 2 on strategies to reduce non-serious side effects, 3 on variables to assess clinical response, and 1 on incorporating patient preferences into decision-making. The level of evidence and the strength of recommendations are reported. Agreement among panelists ranged from 85% to 100%.Conclusion.Nine recommendations pertaining to the use of MTX in daily practice were developed using an evidence-based approach followed by expert/physician consensus with high level of agreement.

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“…Likewise, Furst et al. [3] reported that neither aspirin nor sulindac significantly affected MTX clearance, although no measurement of renal clearance was made. Others have reported that salicylate decreases the total and renal clearances of MTX and increases its fraction unbound in plasma [2,4,5].…”

Section: Introductionmentioning

confidence: 99%

Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis.

Tracy

Worster

Bradley

et al. 1994

Brit J Clinical Pharma

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The effects of three non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics of methotrexate were studied in 10 patients with rheumatoid arthritis.Ketoprofen (3 mg kg-' day-'), flurbiprofen (3 mg kg-' day-'), piroxicam (20 mg day-') or a non-NSAID control (paracetamol/acetaminophen) were administered to patients for at least 6 days (13 days in the case of piroxicam to establish steady state) in a randomized crossover design prior to receiving a weekly oral dose of methotrexate. In the non-NSAID control portion of the study, MTX oral clearance (CLo) was 11.0 ± 3.9 1 h-', renal clearance (CLR) was 7.9 ± 2.8 1 h-1, percent

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Effect of Aspirin and Sulindac on Methotrexate Clearance

Cited by 72 publications

References 22 publications

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

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

Canadian Recommendations for Use of Methotrexate in Patients with Rheumatoid Arthritis

Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis.

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