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Clinical Cancer Research Vol. 12, 536-542, January 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Clinical

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

Christopher J. Sweeney1, Chris H. Takimoto3, Jane E. Latz2, Sharyn D. Baker3, Daryl J. Murry4, James H. Krull2, Karen Fife1, Linda Battiato1, Ann Cleverly5, Ajai K. Chaudhary2, Tuhin Chaudhuri3, Alan Sandler1, Alain C. Mita3 and Eric K. Rowinsky3

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.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
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 Vss 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).

Pemetrexed is a novel antifolate that inhibits three folate-dependent 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 methotrexate-resistant 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 ~80% protein bound, with rapid plasma distribution and elimination phases, and exhibits linear pharmacokinetics over a broad range of doses (0.2-838 mg/m2). The steady-state volume of distribution (Vss) of pemetrexed is small (16 L), suggesting limited tissue distribution. Furthermore, pemetrexed is rapidly eliminated from the plasma by urinary excretion (t1/2 = 3.5 hours), with ~70% to 90% of the administered dose recovered unchanged in the urine within 24 hours (5, 8, 9).

Both aspirin and ibuprofen are nonsteroidal anti-inflammatory drugs (NSAID) commonly used as concomitant medications in cancer patients undergoing chemotherapy. These NSAIDs are known to interact with some antifolates, such as methotrexate (10). Although the mechanism of interaction is unknown, NSAIDs may compete for renal tubular secretion with methotrexate (10, 11), decreasing the renal clearance of methotrexate and increasing systemic exposure, which can lead to increased drug-induced toxicities.

The structure and pharmacokinetics of pemetrexed are similar to those of methotrexate. The primary route of elimination for both pemetrexed and methotrexate is renal excretion of unchanged drug in the urine (8, 12). Like methotrexate, the clearance of pemetrexed is decreased in patients with renal insufficiency (13, 14). For both drugs, decreased clearance results in greater systemic exposure, which may be associated with increased toxicity.

Due to the structural and pharmacologic similarities between methotrexate and pemetrexed, previous clinical trials of pemetrexed excluded patients requiring chronic administration of aspirin or other NSAIDs. This was due, in part, to a reduction in total plasma clearance of pemetrexed observed in the 11th cycle when aspirin was administered concomitantly to one patient enrolled in a phase I study (8). Although this may have been confounded by a reduction in renal function, the possibility of an interaction with NSAIDs or aspirin suggested that further investigation was warranted.

To better understand the potential for drug-drug interactions, two independent drug interaction pharmacokinetic and toxicity studies were conducted to examine the concomitant administration of pemetrexed with either aspirin or ibuprofen. The primary study objectives were to determine the pharmacokinetics of pemetrexed when coadministered with aspirin or ibuprofen and to assess the effect of aspirin or ibuprofen coadministration on pemetrexed-related toxicities.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Eligibility criteria. Patients with a confirmed histologic or cytologic diagnosis of locally advanced or metastatic solid malignancy for which standard treatment options either did not exist or had failed were eligible for enrollment in these two studies. Prior radiation therapy and/or chemotherapy had to be completed at least 30 days before study enrollment (6 weeks for nitrosourea or mitomycin C). Other eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group performance status ≤2, presence of measurable or evaluable disease, estimated life expectancy ≥12 weeks, glomerular filtration rate (GFR) ≥60 mL/min, absolute neutrophil count (ANC) ≥1.5 x 109/L, platelet count ≥100 x 109/L, hemoglobin ≥9 g/dL, bilirubin ≤1.5 times the upper limit of normal, and hepatic transaminases ≤3 times the upper limit of normal (or <5 times upper limit of normal if due to liver disease).

Patients were excluded from study participation for symptomatic or active brain metastases, clinically significant pleural or peritoneal effusions, serum albumin levels <2.0 g/dL, body surface area >3 m2, inability to take folic acid or vitamin B12 supplements, inability to interrupt NSAID therapy, hypersensitivity to aspirin or ibuprofen, prior wide-field pelvic radiation, or a history of or active peptic ulcer disease (aspirin study only).

The studies were conducted according to the most recent version of the Declaration of Helsinki or the applicable guidelines of good clinical practice, whichever represented the greater protection of the patient. The protocols were approved through the respective institutional review boards, and all patients provided written informed consent before treatment.

Study design and treatment. Two independent drug interaction studies were conducted separately at two institutions: the aspirin/pemetrexed interaction study was conducted at the Indiana University Cancer Center (Indianapolis, IN) and the ibuprofen/pemetrexed drug interaction study was conducted at the Cancer Therapy and Research Center at the University of Texas Health Science Center (San Antonio, TX). Both studies used a randomized, crossover, open-label design. Once enrolled, patients were randomized to receive either pemetrexed alone or concurrently with an NSAID for cycle 1. Patients were then crossed over to the opposite treatment for cycle 2.

Pemetrexed (Alimta, Eli Lilly and Co., Indianapolis, IN) was provided as a lyophilized product in a 1:1 ratio with mannitol and was reconstituted with NaCl for injection. Pemetrexed (500 mg/m2) was administered as an i.v. infusion over 10 minutes on day 1 of a 21-day cycle.

In the aspirin study, 325 mg enteric-coated aspirin was administered orally every 6 hours for the designated cycle only, starting 2 days before pemetrexed administration, with the ninth and final dose given 1 hour before pemetrexed administration. In the ibuprofen study, 400 mg (2 x 200 mg) ibuprofen was administered orally using the same schedule.

No other anticancer therapies were permitted during the study. Before each treatment cycle, dexamethasone (4 mg orally twice daily for 3 days, starting the day before pemetrexed administration) was administered as rash prophylaxis. To reduce pemetrexed-related toxicities (15), patients were supplemented with folic acid (350-600 µg orally daily) and vitamin B12 (1,000 µg i.m. every 9 weeks), both beginning 1 to 2 weeks before the first dose of pemetrexed and continuing until the patient completed treatment.

If a patient's creatinine clearance (CrCl) decreased by >25% from baseline or if the patient did not have an ANC ≥1.5 x 109/L and a platelet count ≥100 x 109/L before each course of pemetrexed, treatment was delayed up to 2 weeks. Pemetrexed therapy was continued at the discretion of the investigator following treatment delays. Patients were allowed to continue pemetrexed therapy until any of the following events occurred: progressive disease, unacceptable toxicity, pregnancy or failure to use adequate birth control, or withdrawal as requested by the patient or physician.

Baseline and treatment assessments. Each baseline assessment included radiological studies for tumor assessments, a medical history and physical examination, evaluation of Eastern Cooperative Oncology Group performance status, chest X-ray, complete blood count, comprehensive blood chemistries, urinalysis, measured 24-hour urinary CrCl, estimated CrCl [by the method of Cockcroft and Gault (CrClCG,STD); ref. 16], measured GFR based on technetium-99m diethylenetriamine pentaacetic acid serum clearance, and a vitamin metabolite assay.

A complete blood count and blood chemistries, including liver function tests, blood urea nitrogen, serum creatinine, and CrClCG,STD, were done weekly. In addition, within 4 days before the start of each cycle, a urinalysis was done and serum creatinine was measured for the determination of CrClCG,STD as well as a vitamin metabolite assay and an assessment of drug-related toxicities using the National Cancer Institute Common Toxicity Criteria version 1.0. If any grade 3 or 4 toxicity occurred, the appropriate laboratory tests were repeated every other day to determine the duration of the toxicity. Repeat technetium-99m diethylenetriamine pentaacetic acid GFR evaluations were done during every other cycle of therapy and after any pemetrexed dose reduction or treatment delay. Tumor response assessment, although not required, was evaluated according to Southwest Oncology Group criteria before every other cycle.

Although CrCl was measured (technetium-99m diethylenetriamine pentaacetic acid GFR) and estimated (CrClCG,STD) in the current study, because CrClCG,STD has been shown previously to provide a good approximation of technetium-99m diethylenetriamine pentaacetic acid GFR in this patient population (13), "CrCl" will be used hereafter to refer to either technetium-99m diethylenetriamine pentaacetic acid GFR or CrClCG,STD.

Blood samples for determination of plasma pemetrexed concentration were collected in a 7 mL heparinized tube immediately pre-dose, at the end of infusion, and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours following pemetrexed infusion in both cycles 1 and 2. Samples were analyzed at Taylor Technology, Inc. (Princeton, NJ) for pemetrexed content using a validated liquid chromatography-electrospray ionization with tandem mass spectrometric detection method (17). The plasma sample (0.5 mL) and internal standard ([2H4]pemetrexed) were precipitated with 7% perchloric acid. The samples were centrifuged for 5 minutes at 21,000 RCF. A sufficient amount of supernatant was filtered through a 0.22-µm filter and transferred to an autosampler vial. The sample was chromatographed under reverse-phase conditions on a YMC Basic C8 column using a gradient system with water and acetonitrile containing 0.2% formic acid. Results were calculated using a weighted linear regression of the standard curves [1 / (concentration)2]. The validated standard curve was 0.010 to 2.000 µg/mL. The interassay precision was 6.5% to 10.3% and the interassay accuracy ranged from –3.4% to 10.0%. A second method was validated with an analytic range from 1.000 to 200.000 µg/mL. Except for plasma volume (0.1 mL), details of the second method were identical to those provided for the low-range assay. The interassay precision for the high-range assay was 7.4% to 9.6% and the interassay accuracy ranged from –2.8% and 0.3%. Pemetrexed (for concentrations up to 200.000 µg/mL) was stable in human plasma for at least 26 months upon storage at either –20°C or –70°C.

Statistical and pharmacokinetic analyses. For both aspirin and ibuprofen studies, data from all patients who received at least one dose of pemetrexed were included in the safety analysis. Completion of two treatment cycles (one with and one without concomitant NSAID) was not required for inclusion in the pharmacokinetic analysis comparing pemetrexed pharmacokinetics with and without concomitant NSAID treatment. Patients included in the analysis were those who received pemetrexed treatment, had evaluable dosing information for pemetrexed and aspirin or ibuprofen (if administered), and had evaluable pharmacokinetic sampling data. A planned sample size of 24 patients with a two-way crossover design provided 80% power to detect a 33% difference in pemetrexed clearance between the study groups (pemetrexed + aspirin or ibuprofen versus pemetrexed alone) with a type 1 error of 5%.

Pemetrexed pharmacokinetics were evaluated using noncompartmental methods (WinNonlin Professional, version 3.1, Pharsight Corp., Menlo Park, CA). Pharmacokinetic parameters determined based on plasma concentration versus time data were maximum plasma concentration (Cmax), elimination half-life (t1/2), area under the plasma concentration versus time curve (AUC) from time 0 to infinity (AUC0-{infty}), Vss, and plasma clearance (Clp; ref. 18).

The influence of concomitant aspirin or ibuprofen administration on AUC0-{infty}, Cmax, Clp, and Vss was assessed using a mixed-effects model with patient as a random-effect and treatment regimen (pemetrexed + aspirin or ibuprofen and pemetrexed alone), period, and sequence as fixed effects. The 95% confidence intervals of the ratio of the geometric means for each study group were calculated for AUC0-{infty}, Cmax, Clp, and Vss. All pharmacokinetic parameters were logarithmically transformed before analysis.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Patient characteristics and disposition. Two studies were conducted from December 13, 1999 to June 21, 2001 (aspirin study) and from January 3, 2000 to June 5, 2002 (ibuprofen study); 29 and 30 patients were enrolled, respectively. Table 1 summarizes the demographic data for all patients in each study. The mean ± SD baseline body surface area (m2) for the aspirin and ibuprofen study, respectively, was 1.86 ± 0.273 (range, 1.45-2.60) and 1.88 ± 0.213 (range, 1.45-2.22). The mean ± SD baseline CrCl (mL/min) for the aspirin and ibuprofen study, respectively, was 121 ± 43.3 (range, 71.1-228) and 117 ± 32.9 (range, 61.0-193).


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  		Table 1. Summary of patient demographics and characteristics

 
Of the 29 patients enrolled in the aspirin study, 3 withdrew before the second cycle: 1 due to cellulitis, which was unrelated to the study drug, and 2 due to decreased performance status, which was also unrelated to the study drug. Of the 30 patients enrolled in the ibuprofen study, 1 patient withdrew due to fatigue (possibly related to the study drug) after 18 cycles of treatment. Two patients (one in each NSAID study) died while on-study both due to progressive disease.

Treatment. In the aspirin study, a total of 92 cycles were administered (median, 2; range, 1-13), whereas a total of 219 cycles were administered in the ibuprofen study (median, 3.5; range, 1-22).

In the first two cycles of the aspirin study, no dose omissions or reductions occurred, and only two patients had dose delays for clinical reasons: one due to decreased CrCl and one due to abnormal liver function tests. In the first two cycles of the ibuprofen study, there were no dose omissions, but one patient required a dose reduction for thrombocytopenia and two patients had dose delays for clinical reasons: one due to fatigue and one due to peripheral edema.

Pharmacokinetics. Twenty-seven patients in each study were evaluable for the pharmacokinetic analyses. Two patients in each study were not included in the pharmacokinetic evaluation because NSAID dosing information was not available. One additional patient in the ibuprofen study was not included in the pharmacokinetic evaluation because an underlying medical condition (gastrointestinal hemorrhage) precluded ibuprofen administration.

The mean plasma pemetrexed concentration versus time plots for patients receiving pemetrexed alone and in combination with aspirin were essentially identical (Fig. 1), indicating that concomitant aspirin administration did not influence pemetrexed disposition. A comparison of pharmacokinetic parameters for pemetrexed administered alone and in combination with aspirin revealed no influence of concomitant aspirin administration on the pharmacokinetic profile of pemetrexed (Table 2). The 95% confidence intervals for the ratios of the individual parameters determined for pemetrexed administered in combination with aspirin to those of pemetrexed administered alone all encompassed a value of 1, indicating no statistically significant influence of aspirin on pemetrexed disposition.


Figure 1
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  		Fig. 1. Mean pemetrexed concentration in plasma versus time for pemetrexed plus aspirin or ibuprofen versus pemetrexed alone.

 

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  		Table 2. Least-squares geometric mean values for pemetrexed plus aspirin versus pemetrexed alone and pemetrexed plus ibuprofen versus pemetrexed alone

 
In contrast, mean plasma pemetrexed concentrations for patients treated with ibuprofen were consistently greater than those for pemetrexed administered alone (Fig. 1), suggesting that pemetrexed elimination was reduced by concomitant ibuprofen administration. Administration of ibuprofen with pemetrexed resulted in statistically significant changes in pemetrexed AUC (20% increase), Cmax (15% increase), and Clp (16% decrease) compared with pemetrexed administered alone (Table 2) based on the log-transformed geometric mean ratios of these pharmacokinetic parameters. No statistically significant change in Vss was identified. There was no alteration in CrCl with administration of ibuprofen (117 mL/min for treatment cycles in which pemetrexed was administered alone versus 112 mL/min for treatment cycles in which ibuprofen was coadministered with pemetrexed).

Toxicity. For both studies, pemetrexed therapy was well tolerated (Table 3) and no increase in pemetrexed-related toxicity was associated with NSAID administration.


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  		Table 3. Maximum National Cancer Institute Common Toxicity Criteria grade 3 and 4 toxicities

 
Neutropenia was the most commonly observed hematologic toxicity. In the aspirin study, one patient experienced grade 4 neutropenia and four additional patients had grade 3 neutropenia. In the ibuprofen study, one patient experienced grade 4 neutropenia and five additional patients had grade 3 neutropenia. In both studies, there were no reports of febrile neutropenia, and recovery from neutrophil nadirs to an ANC >1.0 x 109/L occurred in all patients. For patients with grade 3 or 4 neutropenia, the median ANC nadir was 0.66 x 109/L for the aspirin study and 0.85 x 109/L for the ibuprofen study, occurring at a median of 7.0 days after study-drug administration for both studies. The median recovery ANC was 2.40 x 109/L for the aspirin study and 6.05 x 109/L for the ibuprofen study, occurring at a median of 9.0 and 7.0 days later, respectively.

Neutrophil and platelet nadirs for both studies were similar for pemetrexed administered with or without an NSAID (Table 4) and were independent of both the type of NSAID given and the cycle of the NSAID administration. Therefore, there is no evidence that coadministration of NSAIDs with pemetrexed has any effect on myelosuppressive toxicities.


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  		Table 4. Neutrophil and platelet count nadirs in patients treated with pemetrexed with and without aspirin or ibuprofen

 
For both studies, the incidence of nonhematologic toxicities was low (Table 3). In the aspirin study, one patient had grade 4 nausea and vomiting and one patient experienced grade 4 cellulitis, although the cellulitis was not related to the study drug. No grade 4 nonhematologic toxicities occurred in the ibuprofen study.

Responses. In the aspirin study, 1 (3.4%) patient with non–small cell lung cancer had a partial response, 9 (31.0%) patients had stable disease, and 17 (58.6%) patients had progressive disease. In the ibuprofen study, 5 (16.7%) patients with mesothelioma had a partial response, 12 (40.0%) patients had stable disease, and 10 (33.3%) patients had progressive disease.


   Discussion
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 Materials and Methods
 Results
 Discussion
References
 
In the aspirin study, no alteration in pharmacokinetics was identified when pemetrexed was coadministered with 325 mg enteric-coated aspirin to advanced cancer patients with CrCl ≥60 mL/min. Furthermore, pemetrexed clearance and distribution volumes observed in the patients enrolled in the aspirin study were consistent with those seen in 426 patients with solid tumors treated with pemetrexed as a single agent (clearance, 91.8 mL/min; Vss, 16.1 L; ref. 5). Pemetrexed-related toxicities were independent of aspirin administration and no increase in hematologic toxicities was observed. Therefore, no adjustment in pemetrexed dosage is required for patients receiving moderate doses of aspirin.

These conclusions, however, cannot be extrapolated to high-dose aspirin regimens. 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 ~200 µg/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.

In contrast to the aspirin findings, coadministration of 400 mg (2 x 200 mg) ibuprofen with pemetrexed significantly reduced systemic pemetrexed clearance (Table 2). Concomitant administration of ibuprofen with 500 mg/m2 pemetrexed was associated with a 20% increase in pemetrexed AUC, a 15% increase in Cmax, and a 16% reduction in overall clearance; however, there was no significant effect on Vss compared with pemetrexed administered alone. Because of the safety margins inherent in the use of 500 mg/m2 pemetrexed when administered with folic acid and vitamin B12, this modest increase in drug exposure did not increase hematologic toxicities when pemetrexed was coadministered with ibuprofen.

These results parallel those observed when pemetrexed was evaluated in patients with renal dysfunction, in which 9 cancer patients with CrCl values ranging from 41 to 59 mL/min had a mean pemetrexed AUC following a 500 mg/m2 dose that was 59.6% higher than that seen in 11 patients with normal renal function (CrCl ≥80 mL/min) treated at the same dose (13). Despite this large increase in pemetrexed exposure, none of the nine patients with renal impairment experienced excessive toxicities. Because the magnitude of this increase in systemic exposure was much greater than that observed in the ibuprofen-treated patients in the current study, it is unlikely that the 20% increase in pemetrexed AUC is of clinical concern. Thus, dose adjustments are not necessary when ibuprofen is concomitantly administered with the recommended pemetrexed dose of 500 mg/m2 to patients with normal renal function (CrCl ≥80 mL/min).

However, in patients with preexisting reduced pemetrexed clearance due to renal impairment, concomitant ibuprofen administration may further increase pemetrexed exposure. Thus, caution should be used when coadministering ibuprofen with pemetrexed to patients with renal impairment. In the current study, only three patients with CrCl ranging from 60 to 80 mL/min were treated with ibuprofen and pemetrexed. Thus, insufficient clinical data exist to confirm the safety of pemetrexed and ibuprofen in patients with impaired renal function (CrCl <80 mL/min). Similar precautions are recommended when considering ibuprofen coadministration to patients with normal renal function undergoing treatment with higher doses of pemetrexed (>900 mg/m2) administered with folic acid and vitamin B12 supplementation (21).

The precise mechanism by which ibuprofen interferes with the renal elimination of pemetrexed is unknown. At least two potential mechanisms may be responsible for this drug interaction: ibuprofen may compete with pemetrexed for renal tubular secretion or ibuprofen may reduce renal blood flow, thereby causing decreased drug filtration (10). Pharmacokinetic information available at the time of study design (renal clearance ~75% of glomerular filtration for functional kidneys, 80% protein bound; therefore, 20% of GFR represents the maximum contribution of filtration; ref. 8) suggested that tubular secretion was an important component of pemetrexed elimination. Therefore, the design for these studies was optimized to detect an alteration in pemetrexed pharmacokinetics due to competition for renal tubular secretion with steady-state concentrations of aspirin or ibuprofen. A recent pharmacokinetic study of pemetrexed in patients with varying degrees of renal function has indicated that, for patients with normally functioning kidneys, urinary drug excretion is mediated by both tubular secretion and filtration, with tubular secretion being the major component for patients with normal renal function (13). Although it is likely that the interaction that has been characterized in this study is due to competition for renal tubular secretion, pemetrexed urinary excretion data would be required to more specifically characterize the mechanism of the interaction.

Although the structures and pharmacokinetic characteristics of pemetrexed and methotrexate are similar, methotrexate drug interaction studies did not accurately predict the interactions of pemetrexed with aspirin or ibuprofen in our studies. 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).

It is unlikely that the interaction between ibuprofen and pemetrexed can be considered a class effect generally relevant to other NSAIDs. Clinical data are lacking on the effect of other NSAIDs on pemetrexed pharmacokinetics. In the case of methotrexate, coadministration with other NSAIDs has yielded variable findings (22–28). For example, coadministration of high-dose methotrexate with ketoprofen was associated with prolonged and striking enhancement of serum methotrexate levels and was associated with severe and even fatal toxicity (28). In another study, naproxen was shown to decrease methotrexate clearance, but the degree of intersubject variability was quite high (23). In contrast, flurbiprofen, etodolac, piroxicam, and the newer cyclooxygenase-2-specific inhibitors celecoxib and rofecoxib did not alter methotrexate pharmacokinetics (22, 24–27). Thus, in the absence of objective clinical information, general caution should be instituted when considering the coadministration of any other NSAID with pemetrexed.

In conclusion, pemetrexed has minimal myelosuppression and is well tolerated by advanced cancer patients at a dose of 500 mg/m2 with folic acid and vitamin B12 supplementation when coadministered with aspirin or ibuprofen. Cancer patients with CrCl ≥60 mL/min receiving moderate doses of aspirin (325 mg every 6 hours) can be safely administered pemetrexed (500 mg/m2) with folic acid and vitamin B12 supplementation. The same pemetrexed regimen, without dose adjustment, can be given with ibuprofen (400 mg every 6 hours) to patients with CrCl ≥80 mL/min; however, caution should be used when coadministering ibuprofen with pemetrexed to patients with any degree of renal impairment (CrCl <80 mL/min).


   Acknowledgments
 
We thank Patti Moore and Noelle Gasco for substantial writing and editorial support in preparing this article, Donna L. Miller for technical assistance, and Sheila Dropcho, Kathleen Molpus, and the clinic and nursing staffs at the Cancer Therapy and Research Center and the General Clinical Research Center at Indiana University School of Medicine (MO1RR00750) for their assistance in the conduct of this study.


   Footnotes
 
Grant support: Eli Lilly and Co.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Presented in part at the American Society of Clinical Oncology 2001.

Received 8/22/05; revised 10/12/05; accepted 10/26/05.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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