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© 2002 American Society for Clinical Oncology Comparative Pharmacokinetic Study of Continuous Venous Infusion Fluorouracil and Oral Fluorouracil With Eniluracil in Patients With Advanced Solid TumorsByFrom the Mayo Clinic and Foundation, Department of Oncology, Rochester, MN; University of Alabama in Birmingham, Birmingham, AL; and Glaxo Wellcome, Inc, Research Triangle Park, NC. Address reprint requests to Alex A. Adjei, MD, PhD, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; email: adjei.alex{at}mayo.edu
PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU.
PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary
RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state CP and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.
FLUOROURACIL (5-FU) IS an antimetabolite indicated for the treatment of carcinoma of the colon, rectum, breast, stomach, pancreas, and other malignancies. It is currently the most commonly used therapeutic agent for gastrointestinal malignancies. Unfortunately, 5-FU has limited efficacy when administered as a single agent and has not consistently produced improved tumor responses or survival when administered alone or in combination with several standard antineoplastic agents. Approaches to enhance the efficacy of 5-FU include biochemical modulation by agents such as allopurinol, 5-(phosphon-N-acetyl)-L-aspartic acid (PALA), interferon, and leucovorin. Historically, only the use in combination with leucovorin has improved the efficacy of 5-FU, albeit modestly. Recent data however suggest that combining 5-FU and leucovorin with irinotecan leads to improved survival in metastatic colorectal cancer compared with 5-FU and leucovorin.1,2 Other approaches to increase the efficacy of 5-FU include the administration of 5-FU by prolonged continuous venous infusion CVI) and regional administration to the liver and peritoneal cavity.
Although the precise mechanism of action of 5-FU has not been determined, it is likely that the cytotoxic effects of 5-FU are the result of interference with both RNA and DNA. 5-FU is converted intracellularly to 5-fluorouridine triphosphate (FUTP) and to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). FUTP is incorporated into RNA as a fraudulent base causing errors during RNA processing.3 FdUMP binds to thymidylate synthase with greater affinity than the natural substrate and inhibits production of thymidine monophosphate and, thus, DNA synthesis.4 Dihydropyrimidine dehydrogenase (DPD), the first enzyme in the degradative pathway of pyrimidine bases, catalyzes the nicotinamide adenine dinucleotide phosphate–dependent reduction of 5-FU. DPD activity in peripheral-blood lymphocytes differs by at least six-fold among patients and correlates directly with the rate of 5-FU elimination from plasma.5 In addition, DPD varies with the circadian rhythm within individuals, producing mirror-image variations in plasma 5-FU concentrations during continuous infusion.6 Approximately 80% of systemic 5-FU is catabolized by DPD in the liver and other tissues.7 After intravenous administration of a single dose of 5-FU (370 to 560 mg/m2), peak plasma concentrations reach 13 to 130 µg/mL.8 The plasma half-life is approximately 6 to 20 minutes and varies significantly among patients. Within 6 hours of administration, plasma concentrations fall below 0.13 µg/mL, the minimum concentration for in vitro cytotoxicity.9 The major urinary metabolite, Eniluracil is a potent, mechanism-based irreversible inactivator of DPD. It has a Michaelis-Menten constant (Km) of 1.6 µmol/L and inactivates the enzyme with a first-order rate constant of 20 minutes-1 (enzyme half-life = 2 seconds).15 Plasma uracil and thymine, the endogenous substrates of DPD, are markedly elevated in animals treated with low doses of eniluracil.16 Pharmacokinetic results from an absolute bioavailability study of 5-FU and eniluracil show that the absorption of 5-FU is rapid and complete, in contrast to the absorption profile of 5-FU when it is given without eniluracil.17 The inactivation of DPD by eniluracil eliminates the variable bioavailability of 5-FU, prolongs the half-life of 5-FU, and elevates plasma concentrations of uracil and thymine, which are also catabolized by DPD. Nonclinical data also indicate that the absence of 5-FU catabolites seem to increase the therapeutic index of 5-FU.16
The pharmacokinetics of CVI 5-FU with doses of
Patient Selection Patients with histologic or cytologic evidence of metastatic or locally advanced cancer for which there was no curative or life-prolonging therapy were eligible for this study. Eligibility criteria also included age  18 years; Eastern Cooperative Oncology Group performance status  2; chemotherapy regimen completed at least 4 weeks before study enrollment; life expectancy of at least 12 weeks; and adequate bone marrow (platelets 100 x 109 cells/L, absolute neutrophil count [ANC] > 1.5 x 109 cells/L, and hemoglobin 9 g/dL), hepatic (total bilirubin 3 times the upper limit of normal, aspartate transaminase 3.0 times normal [ 6.0 if due to liver disease]), and renal (calculated creatinine clearance 40 mL/min) functions.
Dosage and Administration
Pretreatment and Follow-Up Studies
Analysis of Peripheral Lymphocyte DPD Levels
Pharmacokinetics Specimen collection schedule. Before drug administration on day 7, an intravenous line consisting of either an intravenous catheter or a 19-, 20-, or 21-gauge scalp vein needle was placed in a peripheral vein and kept open by a slow infusion of sterile isotonic saline. Blood samples were drawn before drug administration on days 1, 6, and 7, and at the following times after beginning the intravenous infusion or ingestion of the morning oral dose on day 7: 30, 60, and 90 minutes and 2, 4, 6, 9, 12, 12.5, 13, 13.5, 14, 16, 18, 21, and 24 hours. Urine was collected in a plastic container during the following periods: 0 to 3 hours, 3 to 6 hours, 6 to 9 hours, 9 to 12 hours, and 12 to 24 hours after drug administration on the days of the pharmacokinetic studies. The containers were kept refrigerated during the collection period. Plasma and urine specimens were sent to Triangle Laboratories, Inc (Durham, NC) for analysis. Eniluracil, 5-FU, FBAL, and uracil in plasma and urine were determined by gas chromatography with mass spectrometry detection in the selected ion-monitoring mode. 5-FU, uracil, and eniluracil. 13C,15N-isotopically labeled internal standard solution (50 µL) was added to portions of plasma (0.5 mL) or urine (1.0 mL). The internal standard solution for plasma was a 1:1:1 preparation of 13C,15N–eniluracil (10 µg/mL):13C,15N–5-FU (10 µg/mL):13C,15N-uracil (30 µg/mL). The plasma sample was next diluted with 2 mL of a saturated ammonium sulfate solution and 3 mL 50:50 2-propanol:ethyl acetate. The internal standard solution for urine was a 1:1:2 mixture of 13C415N2-eniluracil (200 µg/mL):13C415N2–5-FU (1,000 µg/mL):13C415N2-uracil (1,000 µg/mL). The urine sample was next diluted with 1 mL of a saturated ammonium sulfate solution and 3 mL 25:25:50 heptane:2-propanol:ethyl acetate. Samples were mixed vigorously and the organic layer transferred to a plastic test tube. After the liquid extraction was repeated a total of three times, the combined organic layers were passed through a Varian Bond Elut LCR (Walnut Creek, CA) sodium sulfate column. The resulting organic extract was evaporated to dryness under nitrogen at approximately 72°C and 12 psi. The plasma and urine extracts were reconstituted by mixing with 25 µL of 5-bromouracil in pyridine solution and 76 µL N-methyl-N-(tert-butyldinethyl silyl)-trifluoro acetamide (MTBSTFA) or 400 µL of 5-bromouracil in pyridine solution and 100 µL MTBSTFA. The supernatant was injected onto an RTX-1701 GC column (0.25-µm film thickness, 30 m x 0.32 mm internal diameter), with a helium gas flow rate at 50 mL/min. The assay was linear over the range of 1.0 to 1,000 ng/mL eniluracil, 1.0 to 1,000 ng/mL 5-FU, and 100 to 6,000 ng/mL uracil in plasma. The assay was linear over the range of 10.0 to 10,000 ng/mL eniluracil, 100 to 100,000 ng/mL 5-FU, and 10,00 to 500,000 ng/mL uracil in urine. FBAL. 13C15N isotopically labeled FBAL internal standard solution (50 µL), 5Nsodium hydroxide solution (100 µL), and S-ethyl-trifluorothioacetate (150 µL) were added to a 1-mL portion of urine. Samples were shaken for 30 minutes at room temperature and acidified with 100 µL of 12Nhydrochloric acid. The sample was extracted twice with 3 mL of ethyl acetate; the combined organic layers were evaporated to dryness under nitrogen at approximately 50°C; and a second derivatization was performed by mixing samples with 500 µL of 1:20 acetyl chloride:butanol solution and heating to 90°C for 15 minutes. The cooled sample was reconstituted with 150 µL of toluene. Supernatant was injected onto a DB-1701 GC column (0.25-µm film thickness, 30 m x 0.32 mm internal diameter). The assay was linear over the range of 10.0 to 1,000 ng/mL FBAL in urine. Data analysis. Noncompartmental analysis was performed using WINNONLIN (Version 1.5; Scientific Consulting Inc, Cary, NC). The terminal elimination rate constant (kel) was calculated by linear least squares regression of the linear terminal elimination phase of the graph of ln (plasma concentration) versus time. Area under the curve (AUC) was determined by trapezoidal approximation from the start of treatment to the last detectable plasma concentration (Clast) with residual area after Clast calculated by AUCr = Clast/kel. The elimination half-life was calculated by t1/2 = 0.693/kel. Plasma clearance (Cl) was calculated by Cl = Dose/AUC.
Statistical Design
A total of 33 patients (Table 1) were enrolled onto this study from July 1998 to July 1999. The median number of courses administered per patient after the first two study periods was one (range, one to five courses). The median age of study participants was 64 years (range, 33 to 77 years). All patients had received prior chemotherapy, and 14 patients had received three or more prior chemotherapy regimens. Nine patients had received prior radiation therapy. Twenty patients had metastatic colorectal carcinoma, four patients had metastatic pancreatic carcinoma, two patients each had breast cancer, gallbladder/bile duct carcinoma, appendix/small bowel carcinoma, and the remainder had a variety of tumors (Table 1).
Toxicity Treatment was well tolerated. The frequency and severity of toxicities were minimal (Fig 1). There were no grade 3 or 4 toxicities during period 1 and period 2, and the only grade 2 toxicities were nausea (arm A) and fatigue (arm B). There was no hematologic toxicity. The only grade 4 toxicity (diarrhea) occurred in period 3 when patients received oral eniluracil/5-FU for 4 out of every 5 weeks (Fig 1C). As can be seen in Fig 1A and 1B, there was no significant difference in toxicity between the two study arms.
Antitumor Activity In this heavily pretreated group of patients, confirmed objective partial responses were noted in three out of 33 assessable patients, whereas another three patients had disease stabilization for 3 months or greater.
Pharmacologic Studies
5-FU and Eniluracil Pharmacokinetics During the 24-hour observation period for CVI 5-FU, plasma concentrations for individual patients fluctuated over a two- to 34-fold range (median, 14-fold) (Fig 2, upper panel). The mean values of the maximum plasma (Cmax), trough plasma (Cmin), and average plasma concentrations (Cavg) during the AM were 229 ± 98 ng/mL, 44 ± 25 ng/mL, and 101 ± 43 ng/mL, respectively (Table 3). A consistent pattern, reminiscent of diurnal variation, was not detected in the fluctuation of the plasma 5-FU concentrations. Although the mean PM Cmax, Cmin and Cavg values were lower, the difference was small.
Peak and trough concentrations were much lower after oral administration, however, individual variability was substantially reduced when drug was administered orally (Fig 2, lower panel). After oral administration of the AM dose, the peak plasma concentration of 71.0 ± 14.7 ng/mL 5-FU was achieved 0.81 ± 0.40 hours after drug administration, and the elimination half-life was 5.05 ± 1.3 hours. The peak plasma concentration, time of peak plasma concentration, and half-life values after the PM dose were lower than the values found after the AM dose, and although the differences were statistically significant (P < .0001), they were small. Interestingly, a statistically significant difference was noted for volume of distribution (Vz/F), but not for apparent oral clearance (Cl/F) and AUC values. After oral administration of the AM dose, the peak plasma concentration of 662 ± 146 ng/mL eniluracil was achieved 1.05 ± 0.5 hours after drug administration and the elimination half-life was 3.7 ± 0.8 hours. As was seen for 5-FU, the peak plasma concentration was lower, the half-life was longer after the PM dose, and the differences were statistically significant (P < .0001), but small. In contrast to 5-FU, statistically significant differences were observed between AM and PM values of AUC, Cl/F, and Vz/F. Finally, mean AUC and Cl/F values were not dependent on the sequence of drug administration (Fig 3).
During the 24-hour continuous infusion, 1.7% ± 0.6% (range, 0.5% to 3.0%) and 66.8% ± 13.4% (range, 25.5% to 120%) of the administered dose was excreted in urine as the parent drug and major urinary metabolite, FBAL, respectively. During administration of oral 5-FU with eniluracil, 70.5% ± 19.1% (range, 35.4% to 102%) and 3.3% ± 3.6% (range, 0.4% to 15.9%) of the administered dose was excreted in urine as the parent drug and major urinary metabolite, FBAL, respectively. The urinary recovery of eniluracil was 48.6% ± 12.0% (range, 25.0% to 72.8%). Recoveries of 5-FU, FBAL, and eniluracil were not dependent on the sequence of continuous infusion and oral drug regimens.
DPD Inactivation by Eniluracil
In the small group of patients that had DPD enzyme activity determined before both treatment regimens (n = 9), enzyme activity could not monitor the return of DPD activity to the normal range because of the small number of paired samples for patients who received the combination tablets first and the high degree of variability in the CVI 5-FU pharmacokinetics. However, this data was useful to illustrate relationships between 5-FU and DPD activity. AUC144-156h was associated with DPD activity when 5-FU was administered by CVI (r2 = 0.5589, P
The pharmacokinetics of CVI 5-FU with doses 300 mg/m2/d have not been well characterized because of limited sensitivity of available assays and high variability caused by fluctuations in DPD activity over a 24-hour period. The exposure to 5-FU during chronic oral dosing of eniluracil/5-FU was expected, but not yet shown, to be equivalent to that during prolonged infusion schedules. We sought to evaluate the pharmacokinetic equivalence of the oral eniluracil/5-FU regimen with a CVI 5-FU regimen using a study design in which patients were randomized to receive either the sequence of oral eniluracil/5-FU followed by CVI 5-FU or the sequence of CVI 5-FU followed by oral eniluracil/5-FU. Each patient received both regimens to serve as his or her own control to minimize the interindividual variability in 5-FU pharmacokinetics and permit evaluation of sequence dependence and DPD inhibition on 5-FU pharmacokinetics. In this group of patients, 5-FU pharmacokinetics, whether administered by CVI or orally with eniluracil, were similar to those reported previously.6,17,24,25 However, the 24-hour systemic exposure and mean steady-state plasma concentration on day 7 were three-fold lower when 5-FU was administered orally compared with continuous infusion. This is not unexpected based on 5-FU pharmacokinetics. In an earlier phase I trial that defined the oral eniluracil and 5-FU doses for prolonged administration schedules, the 5-FU dose predicted to achieve steady-state concentrations equivalent to those of CVI 5-FU was 1.85 mg/m2 administered twice daily.24 This dose was not achieved in their study because of dose-limiting toxicity observed when the eniluracil dose was adjusted to fully inactivate DPD. In a review of 5-FU pharmacokinetics,26 the prominent features of prolonged 5-FU infusion schedules were higher clearance values relative to rapid infusion schedules and substantial variability among the steady-state plasma concentrations found in different studies. Although the mean steady-state concentration of 0.13 µmol/L was used to predict the oral 5-FU dose for the eniluracil/5-FU phase I trial, others have reported steady-state concentrations as low as 0.005 µmol/L18 and as high as 0.57 µmol/L27 during protracted infusion of 300 mg/m2 5-FU. We observed substantial variability in the 5-FU plasma concentration during administration of the continuous infusion, but the mean steady-state concentration of 104 ng/mL (0.80 µmol/L) was above the range noted for protracted infusion schedules. Because of the substantial variability in 5-FU pharmacokinetics and the numerous factors identified that effect 5-FU pharmacokinetics, several recommendations have been made for clinical trials of 5-FU pharmacokinetics.26 Many of these were incorporated into our clinical trial. This trial used a randomized cross-over design in which each patient served as their own control. Patients who received only one of the schedules were not eligible for pharmacokinetic analysis. After administration of oral eniluracil/5-FU, treatment was delayed for 2 to 3 weeks to allow normalization of plasma uracil before starting CVI 5-FU. The specimen collection schedule was identical for each treatment regimen; specimens were drawn on the same day of treatment at the same time of day. These data suggest that a higher oral dose of 5-FU may result in steady-state plasma concentrations equivalent to those obtained during a protracted infusion of a 300-mg/m2 dose. However, the clinical significance of achieving plasma levels similar to CVI 5-FU is unclear at this time, especially as a nonpharmacokinetic-dependent factor in the activity of eniluracil/5-FU may be the reduction of undesirable 5-FU catabolites. If DPD inactivation is to be pursued further as a means of improving the systemic availability and possible activity of 5-FU, additional investigations are required to determine the balance amongst clinical activity, 5-FU dose, DPD inactivation by eniluracil, and toxicity.
Supported by grant nos. CA77112, CA69912, and RR00585 from the National Institutes of Health, Bethesda, MD, and Glaxo Wellcome, Inc, Research Triangle Park, NC. We thank Kim Jensen for excellent data management, Michelle Daiss for protocol management, Jill Piens and the nurses at the Mayo General Clinical Research Center for pharmacokinetic sampling and specimen preparation, Britta Jasperson for data analysis, and Bonny Reinmuth for expert secretarial assistance.
1. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343: 905-914, 2000 2. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355: 1041-1047, 2000[CrossRef][Medline] 3. Mandel HG: The incorporation of 5-FU into RNA and its molecular consequences. Prog Mol Subcell Biol 1: 82-135, 1969 4. Santi DV, McHenry CS, Sommer H: Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13: 471-481, 1974[CrossRef][Medline]
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Harris BE, Song R, Soong SJ, et al: Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res 50: 197-201, 1990 7. Huan S, Pazdur R, Singhakowinta A, et al: Low-dose continuous infusion 5-fluorouracil evaluation in advanced breast carcinoma. Cancer 63: 419-422, 1989[CrossRef][Medline] 8. Finch RE, Bending MR, Lant AF: Plasma levels of 5-fluorouracil after oral and intravenous administration in cancer patients. Br J Clin Pharmacol 7: 613-617, 1979[Medline] 9. Abernethy DR, Alper JC, Wiemann MC, et al: Oral 5-fluorouracil in psoriasis: Pharmacokinetic-pharmacodynamic relationships. Pharmacol 39: 78-88, 1989[Medline]
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Porter DJT, Chestnut WG, Merrill BM, et al: Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J Biol Chem 267: 5236-5242, 1992 11. Beck A, Etienne MC, Chradame S, et al: The role of dihydropyrimidine dehydrogenase and thymidylate synthase in tumor sensitivity of fluorouracil. Eur J Cancer 3A: 1517-1522, 1994
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Milano G, Etienne MC, Renee N, et al: Relationship between fluorouracil systemic exposure and tumor response and patient survival. J Clin Oncol 12: 1291-1295, 1994 13. Hansen R, Quebberman E, Ausman R, et al: Continuous systemic 5-FU infusion in advanced colorectal cancer: Results in 91 patients. J Surg Oncol 12: 453-455, 1989 14. Chang AYC, Most C, Pandya KJ: Continuous intravenous infusion of 5-fluorouracil in the treatment of refractory breast cancer. Am J Clin Oncol 12: 453-455, 1989[Medline] 15. Spector T, Porter DJT, Nelson DJ, et al: 5-Ethynyluracil (776C85), a modulator of the therapeutic activity of 5-fluorouracil. Drugs Fut 19: 565-571, 1994 16. Davis ST, Joyner SS, Baccanari DP, et al: 5-Ethynyluracil (776C85): Protection from 5-fluorouracil-induced neurotoxicity in dogs. Biochem Pharmacol 48: 233-236, 1994[CrossRef][Medline] 17. Baker SD, Khor SP, Adjei AA, et al: Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J Clin Oncol 14: 3085-3096, 2000[Abstract]
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Petit E, Milano G, Levi F, et al: Circadian rhythm-varying plasma concentration of 5-fluorouracil during a five-day continuous venous infusion at a constant rate in cancer patients. Cancer Res 48: 1676-1679, 1988 26. Grem JL: 5-Fluoropyrimidines, in Chabner BA, Longo DL (eds): Cancer Chemotherapy and Biotherapy. Philadelphia, PA, Lippincott-Raven Publishers, 1996, pp 149-202 27. Anderson LW, Parker RJ, Collins JM, et al: Gas Chromatographic-mass spectrometric method for routine monitoring of 5-fluorouacil in plasma of patients receiving low-level protracted infusions. J Chromatogr 581: 195-201, 1992[Medline] Submitted May 1, 2001; accepted November 12, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
–fluoro-ß-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. 
