the Institute for Drug Development at the Cancer Therapy and Research Center
    Nuclear Medicine Department, The University of Texas Health Science Center, San Antonio, TX
    Indiana University Cancer Center
    Eli Lilly and Company, Indianapolis, IN.

    ABSTRACT

    PURPOSE: This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function.

    PATIENTS AND METHODS: Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from  80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12.

    RESULTS: Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and nonsupplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR  80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2.

    CONCLUSION: Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR  40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.

    INTRODUCTION

    Pemetrexed (LY231514; Alimta, Eli Lilly and Co, Indianapolis, IN) is a novel antifolate that inhibits multiple enzymes involved in purine and pyrimidine synthesis. Pemetrexed has a unique pyrrolopyrimidine nucleus, which distinguishes it from methotrexate and other antifolates.1 Compared with methotrexate, pemetrexed has a higher affinity for folypoly--glutamate synthetase.2 This results in the prolonged retention of pemetrexed polyglutamates within cells, thereby enhancing its interaction with target enzymes. Initially, pemetrexed was found to be a specific inhibitor of thymidylate synthase3,4; however, it was recognized subsequently as a potent inhibitor of other key folate-dependent enzymes including dihydrofolate reductase and glycinamide ribonucleotide formyl transferase.5

    These multiple mechanisms of action may explain the greater potency and broader spectrum of antitumor activity of pemetrexed in preclinical studies compared with other antimetabolites such as fluorouracil, methotrexate, or raltitrexed.5,6 In clinical studies, antitumor activity has been observed in patients with malignant mesothelioma and non–small-cell lung cancer (NSCLC), as well as colorectal, pancreatic, bladder, head and neck, cervical, gastric, and breast carcinomas.7-14 Pemetrexed has received regulatory approval in combination with cisplatin for chemotherapy-naive patients with malignant mesothelioma and as a single agent for second-line therapy in advanced NSCLC patients.15,16

    In phase I dose-escalation trials, a 10-minute intravenous infusion of pemetrexed was evaluated using three different schedules: weekly for 4 of 6 weeks, once daily 5 days a week every 3 weeks, and once every 3 weeks.17-19 The principal dose-limiting toxicities (DLTs) for all schedules included neutropenia, thrombocytopenia, fatigue, and dermatitis. Other toxicities consisted of nausea and vomiting, anorexia, diarrhea, and transient elevation of hepatic aminotransferases. On the basis of phase I study results, the recommended phase II dose of single-agent pemetrexed administered without vitamin supplementation was 600 mg/m2 infused over 10 minutes every 21 days.19-21 A subsequent phase II study prompted reduction of the pemetrexed dose recommended for additional evaluation to 500 mg/m2 when a large percentage of patients experienced severe toxicities.8

    Pemetrexed is rapidly eliminated (half-life, 3.5 hours; total systemic clearance, 91.8 mL/min), mainly via the kidneys, with 70% to 90% of the administered drug recoverable in the urine within 24 hours.20-22 Plasma protein binding of pemetrexed is approximately 80%, and the volume of distribution at steady-state is small (approximately 16 L), which is consistent with limited tissue distribution.20-22

    Because pemetrexed is eliminated by renal excretion, this phase I dose-escalation study was undertaken to define the safety and pharmacokinetics (PK) of pemetrexed in patients with advanced solid malignancies and normal or impaired renal function. The principal study objectives were to characterize drug-related toxicities, define the maximum-tolerated dose, and to determine recommended doses in this patient population. Secondary objectives were to examine the effects of renal dysfunction on pemetrexed plasma and urine PK, and to evaluate the antitumor activity of pemetrexed in these patients.

    PATIENTS AND METHODS

    Patient Eligibility

    Patients with advanced solid malignancies for whom standard treatment options did not exist were eligible for this study. Prior radiation therapy and/or chemotherapy had to be completed at least 30 days before study entry (6 weeks for nitrosourea or mitomycin). Other eligibility criteria included age  18 years; an Eastern Cooperative Oncology Group performance status  2; estimated life expectancy  12 weeks; adequate hematopoietic function (absolute neutrophil count  1,500/μL, platelet count  100,000/μL, and hemoglobin  9 g/dL); sufficient hepatic function (total bilirubin  1.5x the upper limit of normal [ULN], AST and ALT  3.0x ULN [AST or ALT  5x ULN if caused by liver metastasis]); and measurable or assessable disease. Exclusion criteria included any of the following: symptomatic or active brain metastasis; serious concomitant systemic disorders incompatible with the study; clinically significant pleural or peritoneal effusion; serum albumin less than 2.0 g/dL; body-surface area more than 3 m2; requirement for renal dialysis; or an inability to take folic acid or vitamin B12 supplementation. The use of aspirin or other nonsteroidal anti-inflammatory agents was not permitted from 2 days before (5 days for longer-acting agents) until 2 days after pemetrexed treatment. Written informed consent was obtained according to federal and local institutional guidelines. The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the applicable guidelines on good clinical practice.

    Study Design

    The study was performed at the Institute for Drug Development at the Cancer Therapy and Research Center and The University of Texas Health Science Center (San Antonio, TX), and the Indiana University Cancer Center (Indianapolis, IN). Patients were stratified into four treatment groups based on their glomerular filtration rate (GFR) as measured within 14 days before dosing by serum technetium-99m diethylenetriamine penta-acetic acid (99mTc-DTPA) clearance. Renal function was also assessed using the standard Cockcroft-Gault formula (CrCLCG,std)23 or the formula based on lean body mass (CrCLCG,LBM).24

    Only the 99mTc-DTPA-measured GFR was used to stratify patients into treatment groups. Group 1, consisting of patients with a GFR  60 mL/min, was divided into subgroups 1A (GFR  80 mL/min) and 1B (60 to 79 mL/min). Groups 2, 3, and 4 consisted of patients with a GFR of 40 to 59, 20 to 39, and less than 20 mL/min, respectively. Group 3 was divided into subgroups 3A (GFR 30 to 39 mL/min) and 3B (GFR 20 to 29 mL/min).

    Starting doses were based on renal-function stratification. Dose escalations in new patients were conducted independently within each treatment group, with final pemetrexed doses not to exceed 600 mg/m2 in any group. Three patients were treated at the initial dose level within each treatment group, and if no cycle-1 DLTs were observed, three additional patients were treated at the next dose level. If one of three initial patients experienced a DLT at any given dose level, then three additional patients were treated at that same dose. If a DLT occurred in at least two patients at any dose level, then dose escalation was halted, and the next three patients enrolled onto that treatment group were treated at the next lower dose level. In treatment groups 2, 3, and 4, the first patient treated at any new dose level was observed for 3 weeks before two additional patients could receive the same dose.

    The maximum-tolerated dose and the recommended treatment dose for each treatment group were defined as the highest dose level at which less than two of six patients experienced DLT in cycle 1. More than six patients could be treated at the recommended dose level in each treatment group to obtain additional information about the tolerability of the dose. DLT was defined as any of the following occurring during cycle 1: grade 4 neutropenia lasting more than 5 days or associated with fever or infection; grade 4 thrombocytopenia; any grade 3 or 4 nonhematologic toxicity except for alopecia, suboptimally treated nausea, vomiting, or diarrhea; and unresolved drug-related toxicity delaying re-treatment more than 2 weeks. Toxicity was graded before every cycle according to the National Cancer Institute Common Toxicity Criteria, version 1.0.

    Drug Formulation and Administration

    Pemetrexed was provided as a lyophilized product in a 1:1 ratio with mannitol in 100- and 500-mg vials. Pemetrexed was reconstituted in sodium chloride for injection and administered on day 1 as a 10-minute intravenous infusion of 150 to 600 mg/m2 every 3 weeks. Dexamethasone 4 mg orally twice a day was administered for 3 consecutive days starting 24 hours before each treatment cycle for hypersensitivity reaction prophylaxis.

    During the study, results from a multivariate regression analysis became available and indicated that an elevated baseline homocysteine level (consistent with subclinical folate deficiency) was highly correlated with more severe pemetrexed toxicities.25 To reduce the more severe drug-induced toxic effects, the protocol was amended to include supplementation of patients with folic acid and vitamin B12. Patients enrolled after December 1999 were instructed to take folic acid 350 to 600 μg or equivalent orally daily and received vitamin B12 1,000 μg intramuscularly every 9 weeks, both beginning approximately 1 to 2 weeks before the first dose of pemetrexed and continuing until the patient completed pemetrexed therapy.

    Supportive therapies included high-dose loperamide for diarrhea, and prochlorperazine and/or 5-hydroxytryptamine-3 receptor antagonists for nausea and vomiting. No other anticancer therapies or experimental medications were permitted during the study.

    Baseline and Treatment Assessments

    Medical histories were recorded and physical examinations were performed pretreatment and weekly. Weekly laboratory evaluations included CBCs with differentials, liver function tests, blood urea nitrogen, and serum creatinine. Serum creatinine measurements were performed using a compensated rate-blanked creatinine assay (modified Jaffe reaction)26 on a Roche Hitachi 747 Chemistry Analyzer (Walpole, MA) at Covance Central Laboratory Services Inc (Indianapolis, IN) using Roche reagents and calibrator. If any grade 3 or 4 laboratory toxicities occurred, the relevant tests were to be repeated every other day. Every other treatment cycle, 99mTc-DTPA GFR evaluations were performed. If the creatinine clearance (CrCLCG,std or 99mTc-DTPA GFR) decreased by more than 25% from the pretreatment value, treatment was delayed for 2 weeks. Additional on-study treatment of these patients could occur at the discretion of the investigators at a dose level determined to be safe for the altered renal function as assessed by a repeat 99mTc-DTPA GFR determination. Radiologic studies for disease assessment were conducted pretreatment and after every other cycle. Tumor response was assessed according to standard Southwest Oncology Group criteria.

    Pharmacokinetic Sampling and Bioanalytic Methodology

    Heparinized blood samples for pemetrexed measurement were collected during cycle 1 before dosing and at 0.17, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours after the start of the drug infusion. Total urine output was also collected over 72 hours during the following time intervals: 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 48 to 72 hours after the start of infusion. Plasma and urine samples were analyzed for pemetrexed at Taylor Technology Inc (Princeton, NJ). Plasma samples were analyzed for pemetrexed using a validated liquid chromatography/electrospray ionization–tandem mass spectrometry method that generated a linear response over the concentration ranges of 10 to 2,000 and 1,000 to 200,000 ng/mL.27 Urine samples were analyzed for pemetrexed using a similar analytic technique validated over the concentration range of 1,000 to 200,000 ng/mL.27 Plasma protein binding (fraction bound) was assessed in vitro by incubating representative predose human plasma samples from each renal function group (eight samples from group 1A; eight samples from group 1B; nine samples from group 2; and one sample from group 4) with [14C] pemetrexed disodium at concentrations of 451 and 4,510 ng/mL followed by ultracentrifugation.

    Pharmacokinetic and Pharmacodynamic Analyses

    Pemetrexed PK 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, the area under the plasma concentration versus time curve (AUC) from time 0 to infinity (AUC0-), volume of distribution at steady-state, and total plasma clearance (CLp).28 The fraction of drug excreted unchanged in urine was calculated by dividing the cumulative amount of pemetrexed excreted unchanged in urine within 72 hours by the administered dose. Renal clearance (CLr) was estimated as the product of fraction of drug excreted unchanged in urine and CLp.28 The relationships between CLp and GFR, and different methods of estimating creatinine clearance (CrCLCG,std and CrCLCG,LBM) were examined using linear regression of the log-transformed clearance values. The predictive performance of the CrCLCG,std and CrCLCG,LBM estimates were evaluated by quantifying bias and precision of the estimates relative to measured GFR. Mean percentage error (MPE) was calculated as a measure of bias, whereas mean absolute percentage error (MAPE) and percentage of estimates within 30% of actual were calculated as measures of precision.29-31 The relationship between indices of pemetrexed exposure (AUC0- and Cmax) and drug-related toxicities, such as percent decrease in blood counts, were explored using a sigmoid maximal effect pharmacodynamic model.28

    RESULTS

    Patient Demographics and Clinical Characteristics

    Between May 1998 and November 2000, 47 patients were enrolled and treated with at least one cycle of pemetrexed (Tables 1 and 2). Of these, 13 patients were supplemented with folic acid and vitamin B12, whereas 34 patients received no vitamin supplementation.

    The target patient accrual goals were met in group 1 (GFR  60 mL/min) and group 2 (GFR 40 to 59 mL/min). However, patient accrual in group 4 (GFR < 20 mL/min) and subgroup 3B (GFR 20 to 29 mL/min) was halted after the only patient treated in group 4 died as a result of severe pemetrexed-related toxicities. Although accrual remained open in subgroup 3A (GFR 30 to 39 mL/min), no patients were enrolled. The mean GFR in groups 1A, 1B, and 2 was 112 mL/min (range, 80 to 151 mL/min), 67.2 mL/min (range, 60.7 to 75 mL/min), and 50.8 mL/min (range, 41 to 59 mL/min), respectively, whereas the group 4 patient had a GFR of 19 mL/min.

    DLTs

    The principal DLT of pemetrexed in this study was myelosuppression, most often neutropenia; thrombocytopenia was less common (Table 3). Grade 4 myelosuppressive toxicities and nonhematologic DLTs (including grade 3 weakness/fatigue in four patients and grade 4 stomatitis in one patient) occurred in both supplemented (n = 2) and nonsupplemented (n = 6) patients.

    In group 1A, no DLTs were observed in the first three patients treated with 500 mg/m2 of pemetrexed. At 600 mg/m2, one patient (nonsupplemented with folic acid and vitamin B12) developed grade 3 neuroconstipation. Although it was unlikely that this toxicity was related to pemetrexed administration, the group was expanded to include four additional patients. Because one of these patients (nonsupplemented) developed grade 4 febrile neutropenia in cycle 1, eight additional patients were treated at 500 mg/m2; two of these eight patients developed DLTs (one grade 4 febrile neutropenia in a vitamin-supplemented patient and one grade 3 fatigue in a nonsupplemented patient). Thus, two of 11 patients treated at 500 mg/m2 and two of seven patients treated at 600 mg/m2 had DLTs. Therefore, 600 mg/m2 was the recommended pemetrexed dose for patients with a GFR  80 mL/min.

    In group 1B, one of eight patients (nonsupplemented) treated with 500 mg/m2 and one of five patients (vitamin supplemented) treated at 600 mg/m2 experienced DLTs (grade 4 febrile neutropenia concurrent with grade 4 thrombocytopenia and grade 3 fatigue, and grade 4 febrile neutropenia, respectively). Because fewer than six total patients were treated at the highest dose level in this group, 500 mg/m2 was the recommended pemetrexed dose for patients with a GFR of 60 to 79 mL/min.

    In group 2, one of six patients (nonsupplemented) treated with 400 mg/m2 experienced dose-limiting grade 3 fatigue. Because one of the first three patients treated with 500 mg/m2 experienced treatment-related grade 4 neutropenia (in cycle 2), six additional patients were treated at this dose level. None of these six patients experienced DLTs; therefore, 500 mg/m2 was the recommended pemetrexed dose for patients with a GFR of 40 to 59 mL/min.

    The only patient enrolled onto group 4 (with a GFR of 19 mL/min) treated with 150 mg/m2 developed DLTs of grade 4 neutropenia, grade 4 thrombocytopenia, grade 4 stomatitis, and grade 3 fatigue, and he died on day 20 of cycle 1. The patient was a 79-year-old male with hormone-refractory metastatic adenocarcinoma of the prostate. He did not have clinical evidence of folate deficiency and was enrolled before amendment of the protocol to include folic acid and vitamin B12 supplementation. As a result, group 4 (GFR < 20 mL/min) and subgroup 3B (GFR 20 to 29 mL/min) were closed to further accrual. Accrual to subgroup 3A (GFR 30 to 39 mL/min) remained open, but no patients were enrolled onto this group.

    A second on-study death occurred in a 67-year-old male with NSCLC assigned to group 1A who was treated with 600 mg/m2 of pemetrexed without vitamin supplementation. This patient developed an acute myocardial infarction during cycle 3; however, this death was considered unrelated to the study drug.

    Hematologic Toxicity

    Non–dose-limiting hematologic toxicities were common, occurred in all treatment groups, and did not correlate with the degree of renal function (Table 4). Grade 4 neutropenia occurred in 15 patients (31.9%), with the neutrophil nadir count typically occurring on day 8 after pemetrexed administration. Recovery was generally observed by day 16 and infectious complications were infrequent and mild (grade 2 fever in three patients [6.4%]). Vitamin supplementation with folic acid and B12 reduced the severity of neutropenia across all dose levels; however, the limited numbers of supplemented patients in each group were not adequate to conduct a meaningful statistical analysis. Febrile neutropenia was noted in four patients (8.5%); most recovered without severe sequelae. During the study, 25 patients (53.2%) required RBC transfusions, and five patients (10.6%) received platelet transfusions.

    Nonhematologic Toxicities

    Grade 3 and 4 nonhematologic toxicities were infrequent and varied in distribution across treatment groups and dose levels. One episode of grade 4 mucositis occurred in the group 4 patient who experienced fatal drug-related toxicity. Four patients developed serious skin toxicities that were highly variable in clinical presentation, including a lower-extremity cellulitis, a generalized maculopapular rash, Schamberg's purpura, and a leukocytoclastic vasculitis. The most frequently reported grade 3 toxicities were neuromotor weakness or fatigue (five patients total, two with vitamin supplementation) and diarrhea (four patients total, one with vitamin supplementation). Other observed grade 3 clinical toxicities included nausea (three patients), pulmonary (one patient), neurocortical (one patient), and constipation (one patient). The distribution of these events did not correlate with renal function (six patients in group 1A, five patients in group 1B, three patients in group 2, and one patient in group 4). GI adverse effects were typically mild, and nausea/vomiting and diarrhea were generally responsive to symptomatic therapies. No evidence of cumulative toxicity was seen. Dose reductions were required in 7.6%, 6.3%, and 3.7% of the 167 administered cycles in groups 1A, 1B, and 2, respectively.

    PK and Pharmacodynamic Evaluation

    PK evaluations were performed using blood samples obtained during cycle 1 from all 47 patients enrolled onto the study (Table 5). The AUC increased in patients with impaired renal function, as demonstrated in Figure 1. Patients with more severely impaired renal function had the longest pemetrexed plasma elimination half-lives (Table 5). In contrast, peak concentrations (Cmax) for a given dose and steady-state volumes of distribution were generally consistent across renal function groups (Table 5). The percent of pemetrexed bound to plasma proteins ranged from 73.4% to 81.0%, and was not affected by renal function or by pemetrexed concentrations.

    Pemetrexed CLp decreased with declining renal function (Tables 5 and 6). Regression analysis of the log-transformed clearance values showed a strong correlation between CLp and the 99mTc-DTPA-measured GFR (slope = 0.888; 95% CI, 0.730 to 1.05; r2 = 0.736; P < .0001; Fig 2A). Consistent with earlier PK studies, unchanged pemetrexed was the predominant drug species excreted in the urine. Cumulative renal excretion of pemetrexed reached a plateau within 12 to 24 hours after drug administration, except for the one group 4 patient with severe renal impairment who demonstrated delayed renal drug excretion (Fig 3). Pemetrexed CLr decreased with declining renal function (Tables 5 and 6). Regression analysis of the log-transformed clearance values showed CLr to correlate with 99mTc-DTPA-measured GFR (slope = 1.52; 95% CI, 1.01 to 2.02; r2 = 0.451; P < .0001; Fig 2B).

    Estimates of CLp and CLr by renal function, based on the regression analyses between CLp and GFR versus CLr and GFR, are summarized in Table 6. Notably, CLr as a proportion of total clearance (ie, CLr/CLp) decreased with decreasing renal function. In addition, clearance due to filtration (unbound fraction x GFR28) as a proportion of overall CLr (ie, [unbound fraction x GFR]/CLr) increased as renal function decreased.

    The PK results have also been evaluated retrospectively relative to body surface area (BSA) –indexed GFR (Table 7). Fifteen patients were reclassified into different renal function groups based on BSA indexing of GFR: four patients from group 1A to group 1B; one patient from group 1A to group 2; seven patients from group 1B to group 2; two patients from group 2 to group 3A; and one patient from group 1B to 1A. The reanalysis (Table 7) yielded similar results to those obtained from the initial evaluation based on unadjusted GFR (Table 5). Moreover, the regressions of log-transformed pemetrexed CLp and CLr versus BSA-indexed GFR showed strong correlations (slope = 0.841; 95% CI, 0.645 to 1.04; r2 = 0.619; P < .0001 for CLp, and slope = 1.39; 95% CI, 0.831 to 1.96; r2 = 0.356; P < .0001 for CLr) that were consistent with the original regressions based on unadjusted GFR. Furthermore, reanalysis of the clinical safety data demonstrated the clinical tolerability of pemetrexed for patients with BSA-indexed GFR  40 mL/min/1.73 m2.

    The pharmacodynamic relationships between pemetrexed exposure as estimated by AUC0- and the decrease in blood counts (WBC count, absolute neutrophil count, and platelet counts) were explored using a maximal effect model. However, no consistent relationships were identified that correlated any PK parameter and drug-induced myelosuppression.

    Antitumor Efficacy

    A 42-year-old male with malignant mesothelioma and a pretreatment GFR of 95 mL/min (group 1A) achieved a confirmed partial response lasting 10.5 months. This patient had been treated previously with three chemotherapy regimens for advanced disease. He received 15 cycles of pemetrexed at 500 mg/m2 and eventually withdrew from the study after developing disease-related pleural effusions. Stable disease was observed in 21 patients (44.7%), and it lasted longer than 3 months (range, 3 to 7 months) in five patients who had primary diagnoses of malignant mesothelioma (n = 1), colorectal carcinoma (n = 2), melanoma (n = 1), and head and neck carcinomas (n = 1). Progressive disease occurred in 17 patients (36.2%), whereas responses were either unknown or not evaluated in eight patients (17.0%).

    Comparison of Renal Function Measures

    Earlier clinical trials of pemetrexed required CrCLCG,LBM more than 45 mL/min for study entry. Our study directly compared the different methods for assessing renal function and showed that the 99mTc-DTPA-measured GFR was better approximated by CrCLCG,std (slope = 0.99; 95% CI, 0.81 to 1.16; r2 = 0.738; MPE = 6.4%; MAPE = 20.5%; 72% of estimates were within 30% of actual) than by CrCLCG,LBM (slope = 0.93; 95% CI, 0.75 to 1.10; r2 = 0.726; MPE = –24.6%; MAPE = 27.1%; 55% of estimates were within 30% of actual). Thus, the estimated CrCL (CrCLCG,std) can be considered equivalent to the measured GFR for assessing renal function in this patient population.

    DISCUSSION

    Single-agent pemetrexed therapy administered as a 10-minute infusion every 3 weeks at doses  500 mg/m2 with vitamin supplementation was well tolerated in patients in group 1A (GFR  80 mL/min), group 1B (GFR 60 to 79 mL/min), and in group 2 (GFR 40 to 59 mL/min). As expected, the major DLTs were hematologic, with four patients developing febrile neutropenia and one patient experiencing prolonged neutropenia (> 5 days). Most pemetrexed-induced toxicities were well tolerated and manageable. Hematologic and nonhematologic toxicities were mild to moderate and were consistent with those reported in other pemetrexed studies.20 These included neutropenia, thrombocytopenia, skin rash, fatigue, diarrhea, and mucositis. Pemetrexed-related toxicities were observed throughout all treatment groups, and the incidence and severity did not correlate with the degree of renal dysfunction in patients with a GFR  40 mL/min. No evidence of any pemetrexed cumulative toxicities or nephrotoxicity was observed. Thus, 500 mg/m2 of pemetrexed with vitamin supplementation can be administered safely to patients with a GFR of 40 to 79 mL/min, whereas patients with a GFR  80 mL/min can tolerate a higher pemetrexed dose of 600 mg/m2. Because the only patient in group 4 (GFR 19 mL/min) died as a result of drug-related toxicities, enrollment was completed only for patients with a GFR  40 mL/min. On the basis of these results, dosing guidelines cannot be recommended for patients with a GFR less than 40 mL/min.

    This study showed that drug clearance was substantially reduced in patients with renal impairment. Pemetrexed CLp values for renally impaired patients in this study were consistent with those for 80 renally impaired patients (CrCL < 80 mL/min) enrolled onto phase II and III studies.22 In this study, pemetrexed CLp varied over a wide range and correlated with the measured GFR (r2 = 0.736). As the GFR decreased from 100 to 40 mL/min, pemetrexed CLp decreased by 56%. As a consequence, pemetrexed systemic exposure increased in patients with impaired renal function. Similar pharmacokinetic characteristics have been reported for methotrexate32 and raltitrexed.33

    For pemetrexed, however, the increase in systemic exposure was not associated with an increase in drug-related DLTs for vitamin-supplemented patients with GFRs  40 mL/min receiving the 500 mg/m2 dose. This tolerability in patients with renal impairment may be attributed to folic acid and vitamin B12 supplementation, which has been shown to reduce severe drug-related toxicities15,34-37 without altering pemetrexed PK.22

    Pemetrexed is eliminated by both tubular secretion and glomerular filtration; however, the relative contribution of these mechanisms to pemetrexed CLr has not been characterized precisely. This study showed that net tubular secretion is the predominant mechanism of pemetrexed CLr for patients with normal renal function (for example, GFR 100 mL/min). Furthermore, the study demonstrated that as renal function decreases, the relative contribution of net tubular secretion to pemetrexed elimination decreases and glomerular filtration becomes the primary mechanism of pemetrexed CLr.

    Tubular secretion typically accounts for an increasing proportion of CLr as renal function declines, which is the opposite of that observed in this study. A number of potential explanations are consistent with these findings. If tubular reabsorption of pemetrexed is substantially increased in patients with diminished renal function, net tubular secretion would decrease. Given that endogenous organic acids are known to accumulate with declining renal function,38 these acids might accumulate sufficiently to compete with pemetrexed for tubular secretion in patients with diminished renal function such that glomerular filtration becomes the primary mechanism of renal elimination. Although the precise transport system(s) responsible for pemetrexed tubular handling is not known, it is known that expression of the kidney-specific organic anion transporters K1 and K2 are decreased in kidney disease in partially nephrectomized laboratory animals.39 It is possible that reduction in these transporters might account for decreased tubular secretion of pemetrexed in our study. Finally, although the underlying cause for renal insufficiency was not documented in this study, the decrease in net renal tubular secretion with decreasing renal function is also consistent with chronic tubulointerstitial diseases such as interstitial nephritis or nephrotoxic injury.

    The current study also compared several measures of renal function. Study stratification was based on the 99mTc-DTPA-measured GFR, which was anticipated to be the most accurate method of quantifying renal function. However, because measured GFR is not easily implemented as a routine clinical test, prediction equations are often used to estimate GFR. Although the CrCLCG,std equation is widely used, and is the recommended method for assessing renal function for drug dosing in US Food and Drug Administration guidances,40 its predictive performance, especially in specific subpopulations, continues to be a topic of research and debate.29,30,41-43 Specifically, CrCLCG,std has been shown to be less accurate in emaciated, highly muscular, or obese patients.28 Early clinical trials of pemetrexed used CrCLCG,LBM as the basis for patient enrollment because cancer patients tend to have a greater proportion of lean body mass and this formula addresses this issue; however, CrCLCG,LBM is a much more complex and cumbersome calculation than CrCLCG,std. In our trial, the CrCLCG,std formula provided a reasonable approximation of the measured GFR, and demonstrated that it is not necessary to use the CrCLCG,LBM formula in this patient population.

    The CrCLCG,std formula resulted in a slight overestimation (MPE = 6.4%) of GFR in the current study, whereas previous reports have indicated that CrCLCG,std may underestimate GFR in cancer patients with normal or mildly impaired renal function.29,44,45 The reason for this disparity is unclear, but may be related partially to different methods for determining serum creatinine. With numerous methods currently in use for the measurement of serum creatinine,46 differences in measurement methodology and lack of calibration across clinical laboratories have been identified as critical limitations to the estimation of GFR by equation,29,47-49 and these factors are estimated to account for prediction errors as high as 20%.47 In our study, creatinine was measured using a compensated rate-blanked creatinine assay (modified Jaffe reaction), which eliminates the overestimation of creatinine that occurs in the unmodified Jaffe reaction.

    In this study, patients were stratified by CrCL uncorrected for BSA; however, pemetrexed dosing recommendations are made on BSA-based calculations. Although it is now increasingly accepted to use a GFR adjusted for BSA as the measure of renal function when drug dosing is based on BSA,50,51 this was not yet a standard practice when this study was planned and conducted. Therefore, for this report, we evaluated the results retrospectively relative to BSA-adjusted GFR. However, these changes did not have an impact on the overall conclusions of the study (Table 7). One possible explanation for the consistency in results between the analysis based on unadjusted GFR and that based on BSA-indexed GFR is the relatively poor correlation between GFR and BSA (r2 = 0.0654; P = .079; slope = 32.2; 95% CI, –3.91 to 68.4) for patients enrolled onto this study, which has also been demonstrated in previous studies.52,53 Second, although pemetrexed is dosed based on BSA as a consequence of clinical development being initiated in the timeframe when such practice was routine, it has now been established that pemetrexed CL is correlated with CrCL, that BSA offers no further explanatory value relative to pemetrexed CL,54 and that toxicity correlates with overall exposure (and therefore, CL).55,56 In addition, the therapeutic index for pemetrexed when administered with vitamin supplementation is considerably enhanced,57 which further explains why the indexing of GFR to BSA does not impact conclusions relative to clinical toxicities for this study. Finally, given that the large majority of reclassifications (14 of 15) resulted in BSA-indexed GFRs that were lower than the absolute GFRs, this reanalysis supports the recommendation of no dose adjustment for patients with a GFR  40 mL/min.

    On a cautionary note, although our current study indicates that dose adjustments are not necessary for vitamin-supplemented patients with renal impairment (GFR  40 mL/min) receiving pemetrexed 500 mg/m2, these findings may not be applicable for higher doses of pemetrexed administered with vitamin supplementation. Emerging data, as shown by preliminary results of an ongoing phase I trial,57 suggest that patients with normal renal function tolerate much higher doses of pemetrexed (up to 1,000 mg/m2 every 3 weeks) in the presence of folate and vitamin supplementation. Future pharmacokinetic and pharmacodynamic evaluations incorporating renal function as a covariate are necessary to better define dosing nomograms appropriate for higher-dose pemetrexed regimens.

    In conclusion, patients with a GFR  80 mL/min tolerated 600 mg/m2 of pemetrexed, whereas patients with a GFR of 40 to 79 mL/min tolerated 500 mg/m2. Systemic pemetrexed clearance correlates with renal function; however, the current study indicates that the corresponding increase in pemetrexed exposure in patients with a GFR  40 mL/min (or CrCL  40 mL/min) is not associated with increased toxicities at doses up to 500 mg/m2. Furthermore, the calculated CrCL using the traditional Cockcroft-Gault method23 is adequate for assessing renal function. Therefore, this study finds that for patients with impaired renal function (GFR  40 mL/min or CrCL  40 mL/min), the recommended vitamin-supplemented pemetrexed dose is 500 mg/m2 every 3 weeks.

    Authors' Disclosures of Potential Conflicts of Interest

    Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

    AuthorsEmploymentLeadershipConsultantStockHonorariaResearch FundsTestimonyOther

    Christopher J. SweeneyEli Lilly and Company (A)

    Anthony W. TolcherEli Lilly and Company (C)

    Alan SandlerEli Lilly and Company (A)Eli Lilly and Company (A)Eli Lilly and Company (A)

    Jane E. LatzEli Lilly and Company (N/R)Eli Lilly and Company (B)Eli Lilly and Company (N/R)

    Lorinda SimmsEli Lilly and Company (N/R)Eli Lilly and Company (A)

    Ajai K. ChaudharyEli Lilly and Company (N/R)Eli Lilly and Company (B)

    Robert D. JohnsonEli Lilly and Company (N/R)

    Chris H. TakimotoEli Lilly and Company (B)

    Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)  $100,000 (N/R) Not Required

    Author Contributions

    Conception and design: Christopher J. Sweeney, Alan Sandler, Tuhin Chaudhuri, Robert D. Johnson, Eric Rowinsky

    Administrative support: Tuhin Chaudhuri, Eric K. Rowinsky

    Provision of study materials or patients: Lisa A. Hammond, Amita Patnaik, Anthony W. Tolcher, Miguel Villalona-Calero, Alan Sandler, Tuhin Chaudhuri

    Collection and assembly of data: Alain C. Mita, Christopher J. Sweeney, Sharyn D. Baker, Andrew Goetz, Lisa A. Hammond, Amita Patnaik, Anthony W. Tolcher, Miguel Villalona-Calero, Alan Sandler, Tuhin Chaudhuri, Kathleen Molpus, Jane E. Latz, Ajai K. Chaudhary, Eric K. Rowinsky, Chris H. Takimoto

    Data analysis and interpretation: Alain C. Mita, Christopher J. Sweeney, Sharyn D. Baker, Andrew Goetz, Lisa A. Hammond, Tuhin Chaudhuri, Jane E. Latz, Lorinda Simms, Ajai K. Chaudhary, Robert D. Johnson, Eric K. Rowinsky, Chris H. Takimoto

    Manuscript writing: Alain K. Mita, Christopher J. Sweeney, Sharyn D. Baker, Lisa A. Hammond, Alan Sandler, Tuhin Chaudhuri, Jane E. Latz, Lorinda Simms, Eric K. Rowinsky, Chris H. Takimoto

    Final approval of manuscript: Alain C. Mita, Christopher J. Sweeney, Sharyn D. Baker, Andrew Goetz, Lisa A. Hammond, Amita Patnaik, Anthony W. Tolcher, Alan Sandler, Tuhin Chaudhuri, Kathleen Molpus, Jane E. Latz, Lorinda Simms, Eric K. Rowinsky, Chris H. Takimoto

    Acknowledgment

    We thank Patti Moore and Noelle Gasco for writing and editorial assistance; Diana Kelley for technical support; Sheila Dropcho, Karen Fife, Linda Battiato, and the staffs of the Cancer Therapy Research Center and the Indiana University Medical Center, for assistance with study conduct.

    NOTES

    Supported by Eli Lilly and Company.

    Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001, and the 27th European Society for Medical Oncology Congress, Nice, France, October 18-22, 2002.

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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