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© 2000 American Society for Clinical Oncology Phase I Assessment of the Pharmacokinetics, Metabolism, and Safety of Emitefur in Patients With Refractory Solid TumorsFrom the US Oncology; Sammons Cancer Center, Baylor University Medical Center; and Mary Crowley Medical Research Center, Dallas; and M.D. Anderson Cancer Center, Houston, TX; Otsuka America Pharmaceutical, Inc., Palo Alto, CA; Otsuka America Pharmaceutical, Inc., and United States Food and Drug Administration, Division of Oncology Drug Products, Rockville; University of Maryland Greenbaum Cancer Center, Baltimore, MD; and University of Washington Medical Center, Seattle, WA. Address reprint requests to John Nemunaitis, MD, US Oncology, 3535 Worth St, Collins Bldg, 5th Floor, Dallas, TX 75246; email john.nemunaitis{at}usoncology.com
PURPOSE: To determine the toxicities, dose-limiting toxicities (DLT), maximum-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in patients with advanced solid tumors. METHODS: This was a phase I dose-escalating trial in which cohorts of patients received BOF-A2 (cohort 1, 300 mg/m2 orally [PO] tid; cohort 2, 200 mg/m2 PO tid; cohort 3, 200 mg/m2 bid; and cohort 4, 250 mg/m2 bid) for 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetics, toxicity, and tumor response were monitored.
RESULTS: Nineteen patients received 110 cycles (three patients in cohort 1, three patients in cohort 2, 10 patients in cohort 3, and three patients in cohort 4). DLT (grade 3 stomatitis, diarrhea, leukopenia) was observed in cohorts 1, 2, and 4. Pharmacokinetics indicated that prolonged systemic expression of fluorouracil (5-FU) is maintained after administration of BOF-A2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was CONCLUSION: BOF-A2 at a dose of 200 mg PO bid for 14 days followed by 7 days of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidence of circadian variation. Furthermore, evidence of antitumor activity is suggested.
EMITEFUR (BOF-A2) IS AN oral fluoropyrimidine intended to act as an orally administered source of prolonged systemic fluorouracil (5-FU) exposure, similar to that attained by 5-FU infusion. It was designed to overcome dihydropyrimidine dehydrogenase (DPD)–dependent circadian rhythm and variability and to improve constant intracellular 5-FU concentrations to potentially reduce toxicity. BOF-A2 is an oral prodrug of 5-FU and 3-cyano-2,6-dihydropyrimidine (CNDP).1-4 It is rapidly broken down to its 1:1 molar components, 1-ethoxymethyl-5-fluorouracil (EM-FU) and CNDP, primarily by esterase. CNDP is a competitive inhibitor of DPD with a potency of 2,000 times that of uracil in vitro.5 EM-FU is further metabolized to 5-FU by microsomal enzymes in the liver. CNDP seems to successfully inhibit DPD maintaining 5-FU concentrations without exhibiting circadian variation.6,7 By avoiding high-peak 5-FU concentrations and decreased accumulation of toxic metabolites, BOF-A2 may be associated with an enhanced safety profile compared with that of other fluoropyrimidines. Clinical studies with BOF-A2 were initiated in Japan. Antitumor activity was observed in patients with solid tumors who received a total daily dose of up to 400 mg/d for up to 28 days, although toxicity related to leukopenia, diarrhea, and anorexia was also observed.8 However, in a subsequent study, antitumor activity was observed in patients with advanced non–small-cell lung cancer at a dose of 200 mg/m2 twice daily with better tolerability. Of 62 assessable patients, 11 partial responses were documented, with an overall response rate of 18%.9 Monitoring of plasma CNDP levels revealed a terminal half-life (t1/2) of 6 to 8 hours, suggesting that a tid schedule may maintain more constant plasma levels of CNDP. The current study was performed to determine the maximum-tolerated dose and pharmacokinetic profile of BOF-A2 in patients with nonresectable solid tumors.
Patients Enrollment criteria for the study included histologically confirmed nonresectable solid tumors for which 5-FU therapy was indicated. Patients had to be at least 18 years of age. Women of childbearing potential could be treated but must have had a negative serum or urine pregnancy test documented within 72 hours before the initiation of treatment. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, measurable or assessable disease, and exhibit adequate bone marrow function (absolute granulocyte count  1,500/µL and platelet count 100,000/µL). Patients were required to have adequate renal and hepatic function (total bilirubin  2.4 mg/dL, AST 2.5 times the upper limit of normal [or 85 U/L for female patients and < 90 U/L for male patients], and ALT 2.5 times the upper limit of normal [or 80 U/L for female patients and < 87.5 U/L for male patients]). Patients with liver metastases were allowed to have and AST level of 5 times the upper limit of normal and adequate renal function (serum creatinine 1.5 mg/dL). Signed informed consent was required for all patients.
Investigational Agent
Study Design BOF-A2 was administered in 100-mg capsules orally every 8 hours (tid) or every 12 hours (bid) according to the treatment cohort. A cycle of therapy was defined as 14 consecutive days of treatment followed by a 1-week rest with a total cycle duration of 21 days. This treatment regimen was based on phase II solid tumor studies in Japan evaluating 4-, 3-, and 2-week administration of BOF-A2 at 150 to 200 mg/m2/d bid. According to toxicity profiles of these trials, 14 consecutive days of treatment was suggested as the most reasonable regimen.8 Days on which BOF-A2 was withheld because of toxicity counted as treatment days.
Specimen Collection and Analysis Plasma and urine specimens were analyzed for EM-FU using validated reverse-phase high-performance liquid chromatography (HPLC) methods with ultraviolet detection. BOF-1651 was used as an internal standard. Internal standard and saturated ammonium sulfate were added to plasma or urine specimens (0.1 mL) and the mixture was then subjected to liquid/liquid extraction with dichloromethane. The organic layer was dried and reconstituted in a 33 mmol/L pH 6.0 sodium phosphate monobasic solution. For urine specimens, the reconstituted solution was rinsed with methyl-t-butyl ether. The organic solvent was then dried and the residue reconstituted in a 33 mmol/L pH 6.0 sodium phosphate monobasic solution. Extracts from plasma were subjected to HPLC separation using a YMC A-302 ODS column (150 mm x 4.6 mm, 5 µm [YMC, Inc, Wilmington, NC]; 10:1:89 acetonitrile:acetic acid:water mobile phase at 1 mL/min flow rate), whereas the HPLC separation for extracts from urine was accomplished with a Waters Symmetry C18 column (Waters Corp, Milford, MA; 150 mm x 4.6 mm, 3.5-µm film thickness; 6:4:89.5:0.5 acetonitrile:methanol:water:acetic acid mobile phase at 0.7 mL/min flow rate). EM-FU was quantitated using ultraviolet detection at 280 nm. The mean retention times for EM-FU and the internal standard were 6.09 and 10.22 minutes, respectively, for plasma extracts, and 9.95 and 15.53 minutes, respectively, for urine extracts. The calibration curves were obtained by weighted (1/concentration) least-squares regression analysis. The specificity of the methods was confirmed by testing blank plasma and blank urine. The plasma method was validated over a linear range of 30 to 10,000 ng/mL, whereas the urine method was validated over a linear range of 100 to 10,000 ng/mL. The mean recovery was 94.1%, inter- and intraday precision was less than 7.5%, and the deviation from nominal values was less than 5.6% for the plasma method. For the urine method, mean recovery was 76.1%, inter- and intraday precision was less than 12%, and the deviation from nominal values was less than 3.2%. Plasma specimens were analyzed for 5-FU using a validated reverse-phase HPLC system with ultraviolet detection. Chlorouracil was used as an internal standard. Specimens (0.1 mL) containing added internal standard were subjected to protein precipitation by addition of saturated ammonium sulfate, followed by liquid/liquid extraction with dichloromethane. The aqueous layer was re-extracted with ethyl acetate. The organic solvent was then dried and reconstituted in a 33 mmol/L pH 6.0 sodium phosphate monobasic solution and subjected to HPLC separation using a YMC AQ-302 column (150 mm x 4.6 mm, 5-µm film thickness; 0.005 mol/L pH 5 sodium phosphate monobasic mobile phase at 1 mL/min flow rate) with ultraviolet detection at 280 nm. The mean retention times for 5-FU and the internal standard were 6.63 and 13.68 minutes, respectively. The calibration curves were obtained by weighted (1/concentration) least-squares regression analysis. The specificity of the method was confirmed by testing blank plasma. The method was validated over a linear range of 10 to 1,000 ng/mL. The mean recovery was 59.1%, inter- and intraday precision was less than 12.8%, and the deviation from nominal values was less than 5.1%. Urine specimens were analyzed for 5-FU by validated gas chromatography using mass selective detection. 15N2-fluorouracil was used as an internal standard. Internal standard was added to specimens (0.025 mL), which were diluted 10-fold with water and subjected to liquid/liquid extraction with ethyl acetate. The organic solvent was then dried, reconstituted in acetonitrile, and derivitized for 30 minutes with pentafluorobenzylbromide and triethylamine at room temperature. The derivative compounds were extracted into an ethyl acetate:hexane admixture (1:10), which was then dried. The residue was reconstituted with ethyl acetate and injected on a Supelco SPB-5 capillary column (15 mm x 0.32 mm, 0.25-µm film thickness [Supelco, Inc, Bellefonte, PA]; helium carrier gas at 1 mL/min; injection port temperature 250°C; temperature program 100°C for 1 minute, 40°C/min to 200°C, 20°C/min to 260°C, 40°C/min to 300°C, and hold for 1 minute). Compounds were detected using a mass selective detector with negative chemical ionization (methane reagent gas). The approximate retention time for 5-FU and the internal standard was 5.2 minutes, and the ions detected were 309 m/z and 311 m/z, respectively. The calibration curves were obtained by weighted (1/concentration) least-squares regression analysis. The specificity of the method was confirmed by testing blank urine. The method was validated over a linear range of 1.00 to 400 ng/mL. The mean recovery was 74.2%, inter- and intraday precision was less than 11.4%, and the deviation from nominal values was less than 8.3%.
Plasma and urine samples were analyzed for CNDP using a validated reverse-phase HPLC system with fluorescence detection. BOF-1583 was used as an internal standard. Plasma specimens containing internal standard were subjected to protein precipitation by acetonitrile addition, and the supernatant was dried. Plasma extracts were reconstituted in, and urine specimens containing internal standard were diluted with, the mobile phase (1% acetonitrile, 99% 0.1 mol/L ammonium acetate, pH 5.0). Reconstituted plasma extracts were subjected to HPLC separation using a YMC ODS-A column (C18, 150 mm x 4.6 mm, 5 µm, mobile phase flow rate of 1 mL/min), whereas the HPLC separation for diluted urine was accomplished using a YMC A302 column (150 mm x 4.6 mm, 5-µm film thickness, mobile phase flow rate of 1 mL/min). CNDP was quantitated using fluorescence detection (
Pharmacokinetic Evaluation
The following pharmacokinetic parameters were calculated for the metabolites of BOF-A2: maximum concentration (Cmax); time when Cmax occurs (tmax); minimum concentration (Cmin; at 24 hours after the first daily dose for day 1, or before the first daily dose on day 14); area under the concentration time curve during a dosing interval (AUCt), calculated using the linear trapezoidal rule; estimated from the observed accumulation (t1/2; ratio of day 14:1 Cmin); apparent clearance of metabolite from plasma after extravascular administration for day 14 (CL/F), determined as dose (expressed as equivalents of the metabolite) divided by AUC
Tumor Response Assessment
Toxicity Assessment Weekly study evaluation included a complete blood cell count, differential, electrolyte, renal function, and liver function testing. Clinical assessment of adverse events, concurrent illness, and changes in concomitant therapies was performed. Additional assessments were taken on day 1 of each 21-day cycle and included physical examination, weight, and performance status assessment, serum electrolytes/chemistries (Na, K, CO2, blood-urea nitrogen, creatinine, total protein, albumin, glucose, alkaline phosphatase, bilirubin, AST, ALT, lactate dehydrogenase, calcium, uric acid, inorganic phosphorus) and urinalysis. Tumor assessment by computed tomography scan was performed on day 21 of each third cycle and on study termination. The evaluations outlined above were repeated for all subsequent treatment cycles as well as at termination of therapy with BOF-A2.
Statistical Analysis
Patient Demographics Nineteen patients with advanced carcinoma received 109 cycles of BOF-A2 at doses ranging from 200 mg/m2/d bid given as a divided dose to 300 mg/m2/d tid given as a divided dose. Patients were treated in the Mary Crowley Medical Research Center at Baylor University Medical Center (Dallas, TX), M.D. Anderson Cancer Center (Houston, TX), University of Washington Medical Center (Seattle, WA), and University of Maryland Greenbaum Cancer Center (Baltimore, MD). Patients in cohort 1 (n = 3) received BOF-A2 at a dose of 300 mg/m2/d tid, patients in cohort 2 (n = 3) received 200 mg/m2/d tid, patients in cohort 3 (n = 10) received 200 mg/m2/d bid, and patients in cohort 4 (n = 3) received 250 mg/m2/d bid. Four patients had an ECOG score of 0, 13 had an ECOG score of 1, and two had an ECOG score of 2. The clinical characteristics of each patient are listed in Table 1. Ten patients received prior 5-FU (two as adjuvant therapy).
Toxicity Of the first three patients enrolled in cohort 1, two were terminated from the study because of DLT (diarrhea [day 14], leukopenia [day 19], and stomatitis [days 13 and 15]) in the first cycle; therefore, the dose of BOF-A2 was decreased to 200 mg/m2/d tid (cohort 2), and three patients were entered. Two of three cohort 2 patients experienced DLT at the end of the first cycle of treatment (diarrhea [days 13 and 14], leukopenia [day 15], thrombocytopenia [day 16], hypotension [day 16], and gastrointestinal hemorrhage [day 21]). Thus the treatment schedule was changed from tid to bid. The following three patients were enrolled in cohort 3 and no unacceptable toxicity was reported in the first cycle. Three additional patients were added to cohort 3 without any DLT. Three patients were then enrolled in cohort 4 (250 mg/m2/d bid). Two of the three patients treated with BOF-A2 at a dose of 250 mg/m2/d bid in cycle 1 experienced DLT (diarrhea [day 17] and stomatitis [day 9]). Further dose reduction to 200 mg/m2/d bid was instituted. Four additional patients were entered into cohort 3. One patient in cohort 3 experienced DLT (rash), however, she inadvertently received a 300 mg/m2 dose in cycle 1 for 10 days. At cycle 2, the 200 mg/m2 bid dose was administered and the rash did not recur. A summary of serious adverse events that caused withdrawal or dose reduction is listed in Table 2. Most frequent ( 20% within all cohorts) adverse events included anemia (21%), anorexia (32%), asthenia (63%), constipation (26%) diarrhea (74%), dyspepsia (26%), peripheral edema (32%), epistaxis (22%), fever (26%), lacrimation (21%), leukopenia (21%), nausea (63%), abdominal pain (47%), back pain (37%), palmar plantar erythrodysesthesia (21%), rash (47%) rhinitis (26%), stomatitis (53%), and vomiting (37%). Toxicity was further assessed by comparing extent of exposure according to cohort and according to actual dose administration. From either perspective, the number of days on treatment substantially increased and delays in treatment were reduced in patients treated in cohort 3 (200 mg/m2/d bid). Specifically, patients entered into cohort 3 had 101 cumulative treatment days compared with 37 to 63 days in all other cohorts. Additionally, cohort 3 patients were able to be restarted on the next cycle of treatment within 9 days compared with 10 to 23 days for all other cohorts. A summary of adverse events according to cohort is listed in Table 3.
Pharmacokinetics For patient no. 116, pharmacokinetic profiles were not obtained on days 1 or 14 of the first treatment cycle. For all other patients, at least one pharmacokinetic profile was obtained in the first treatment cycle. The mean plasma 5-FU concentration time profile is illustrated in Fig 1 for days 1 and 14. On the basis of the plasma BOF-A2 metabolite concentrations for predose specimens collected on days 1, 7, 13, and 14 of treatment cycle 1, steady-state was attained by the seventh day of treatment for all cohorts, as shown in Fig 2.
The pharmacokinetic parameters for the BOF-A2 metabolites on days 1 and 14 are summarized in Table 4. For CNDP, there was little or no accumulation (mean Rac ranging from 0.81 to 1.72), whereas that for 5-FU was marginal and variable (mean Rac ranging from 1.12 to 2.62). In contrast, EM-FU accumulation was marked, with mean Rac ranging from 2.55 to 4.87. Overall, the steady-state plasma EM-FU concentration-time profile showed little fluctuation during a dosing interval, with Cmax only 20% greater than Cmin, for cohorts 1, 2, and 3. The peak-to-trough fluctuation was greater for 5-FU and CNDP, ranging from less than two-fold to nearly three-fold across treatment cohorts. The differences in accumulation or degree of fluctuation between EM-FU and 5-FU or CNDP reflects the differences in t1/2 among the Emitefur metabolites, which were similar for 5-FU and CNDP and generally less than that for EM-FU. The mean tmax for 5-FU (range, 1.0 to 8.1 hours) tended to coincide with that for EM-FU (range, 2.9 to 10.0 hours). For each of the BOF-A2 metabolites, CL/F was similar across cohorts, indicating that pharmacokinetics were linear over the dose range. Less than 10% of the administered dose was excreted in the urine as either 5-FU or EM-FU, which is consistent with the known clearance of these drugs. Approximately 30% to 40% of the dose was excreted in the urine as CNDP.
To evaluate within-day variability of DPD inhibition during BOF-A2 therapy, ratios of steady-state through 5-FU concentrations were calculated for the second and third daily dose on day 14 relative to the first daily dose on day 14. Because the data were expressed as ratios, it was possible to combine data across dose levels within dosage regimens. The results are listed in Table 5. The median ratios range from 0.85 to 1.02. Based on the 95% confidence intervals, the ratios were not significantly different from 1.0 at any time after dose. Because the trough concentrations within a day could be expected to change if clearance were altered, it seems that 5-FU CL/F was unchanged throughout the day, implying that metabolism did not vary. This provides indirect proof that BOF-A2 delivers sufficient CNDP to suppress circadian variation in DPD activity.
Despite accumulation within the treatment cycle, specimens collected before the first dose of the second or third cycles of therapy generally did not contain measurable concentrations of BOF-A2 metabolites. CNDP was not measurable in any specimens after the washout period (days 15 through 21 of the treatment cycle). In a minority of patients, low concentrations of 5-FU (less than twice the limit of detection) were detected after the washout period. EM-FU was detectable in a larger proportion of the specimens collected after the washout period. However, the concentrations detected were less than 5% of the mean day 14 EM-FU Cmax, indicating that the majority of EM-FU was eliminated during the washout period. Overall, the 7-day drug-free period in each treatment cycle seems to provide a sufficient drug washout.
Antitumor Activity
5-FU, a thymidylate synthetase (TS) inhibitor, has remained the mainstay of chemotherapy for treatment of advanced colorectal cancer since the 1950s.11 Single-agent response rates in treatment of epithelial tumors range from 10% to 30%.12 Cytotoxicity of 5-FU in vivo is related to intracellular concentration and duration of exposure. However, clinical toxicity is both dose- and schedule-dependent. Achievement of high peak systemic concentrations are associated with greater clinical toxicity, whereas lower concentrations administered over a prolonged duration are associated with reduced toxicity,13 and recent meta-analyses data suggest that continuous 5-FU administration (prolonged exposure) may be more effective14 as well as less toxic15 than bolus 5-FU, thereby providing a rationale for agents that provide a prolonged duration of exposure of 5-FU. Clinical trials have explored both oral and intravenous (IV) 5-FU administration schedules.14-18 More consistent pharmacokinetic parameters are achieved with IV administration of 5-FU.17-21 Despite potential to provide prolonged exposure, oral 5-FU was abandoned because of erratic absorption related to varying levels of DPD found in the gastrointestinal tract18 and effects related to circadian rhythm variation of DPD. DPD is the primary catabolic enzyme of 5-FU. Pharmacokinetic analysis suggested that administration of oral 5-FU is associated with higher concentrations in the portal circulation and that hepatic metastases seem to be more responsive to oral rather than IV 5-FU.17 Nevertheless, IV administration of 5-FU was adopted, although consensus for the optimal dose, rate of infusion, and duration of administration remains controversial. Common dosing regimens involve a daily bolus schedule for 5 consecutive days, a once-a-week bolus schedule, and a continuous infusion schedule.11,18,22 Neutropenia is associated with bolus schedules, whereas stomatitis and palmar-plantar erythrodysesthesia (hand-foot syndrome) are associated with continuous or protracted infusion.15,20,21 Approximately one third of patients will develop grade 3 or 4 toxicity and 20% to 30% of patients treated are hospitalized for toxic effects with bolus infusion schedules.23,24 Significant toxic effects are much less evident with protracted infusion 5-FU. Intracellular concentrations of 5-FU vary depending on metabolism, tumor cell uptake, and intracellular degradation.25 A new generation of TS inhibitors, such as capecitabine (Xeloda; Roche, Nutley, NJ) or uracil and tegafur (UFT; Bristol-Meyer Squib, Princeton, NJ), have been designed to improve tumor intracellular concentrations and duration of exposure to 5-FU.26,27 Capecitabine is a fluoropyrimidine carbonate that is metabolized by thymidine phosphorylase (TP) to 5-FU.28 UFT is a 4:1 combination of uracil and tegafur. Tegafur is an oral 5-FU prodrug that is rapidly absorbed followed by conversion to 5-FU by cytochrome P450 enzyme in the liver and by TP in tumor tissue.13 Uracil is a normal substrate for DPD and competes with 5-FU, thereby reducing 5-FU clearance.13 Response rates and clinical toxicity with both capecitabine and UFT are similar to prolonged low-dose 5-FU continuous infusions rather than bolus 5-FU.29-34 Their toxicity primarily involves diarrhea and stomatitis. Additionally, capecitabine has an increased occurrence of palmar-plantar erythrodysesthesia.29,35,36 DPD has a five-fold circadian variation that correlates directly to plasma 5-FU concentration.37 Because both 5-FU and uracil are catabolized by DPD, circadian regulation may unpredictably attenuate plasma 5-FU levels, leading to toxic events.
BOF-A2 is a rationally engineered, metabolically activated, DPD-inhibiting fluoropyrimidine designed to provide prolonged 5-FU expression and overcome DPD-dependent circadian rhythm variability. The results in this study confirm that oral administration of BOF-A2 achieved prolonged systemic exposure to 5-FU. For each cohort, mean steady-state plasma 5-FU concentrations were
A dose of 200 mg/m2/d for 14 days of BOF-A2 administered orally in two divided doses seems to be well tolerated in patients with nonresectable solid tumors. The most frequent adverse events observed at this dose level were grade 1/2 nausea, diarrhea, asthenia, stomatitis, and anorexia, all of which are consistent with 5-FU–related toxicity. Neutropenia and myelosuppression complications were remarkably infrequent. Responding patients were monitored for up to 17 cycles without significant hematopoietic dysfunction. At dose levels of There was no strong relationship between BOF-A2 metabolite pharmacokinetics and DLT, although there was modest suggestion of high peak and high trough concentrations of plasma 5-FU during cycle 1 within the tid higher dose cohorts. Activity related to BOF-A2 was suggested in several patients on the basis of a partial response of 337 days in one patient (with an adenocarcinoma of unknown primary, which previously progressed on treatment with carboplatin/paclitaxel) and prolonged maintenance of stable disease in seven other patients. BOF-A2 has a similar mechanism of action as other oral fluoropyrimidines (UFT, capecitabine).8,27,40 The DPD inhibition component of BOF-A2 (CNDP) is suggested based on preclinical studies5 to have a greater inhibiting effect than uracil, which is the inhibiting component of UFT. Furthermore, this study suggests that BOF-A2 may affect circadian variability of DPD activity, which should lead to less variability in plasma 5-FU concentrations. It has not been shown that UFT attains suppression of circadian variability in DPD activity.41 BOF-A2–treated patients showed a modest difference in toxicity, in comparison with capecitabine, based on a less frequent observation of palmar-plantar erythrodysesthesia. Another new oral fluorinated pyrimidine, S-1 (BMS-247616), which is a combination of tegafur and two 5-FU modulators (5-chloro-2,4-dihydroxypyridine to inhibit DPD and potassium oxonate to decrease gastrointestinal tract toxicity) is in phase II investigation. Results reveal a mild toxicity profile with diarrhea as the primary DLT, although leukopenia was occasionally observed.16,42 As noted previously, myelosuppression was a notably infrequent component of BOF-A2 toxicity. The fluoropyrimidines, which are metabolized by DPD, may have a reduced occurrence of palmar-plantar erythrodysesthesia overall in comparison with IV 5-FU or capecitabine, possibly related to reduced catabolite products of 5-FU, which are prevented by DPD inhibition.14,15,27,40-42 Eniluracil is an irreversible inactivator of DPD.45 When used in combination with oral 5-FU, eniluracil improves absorption and bioavailability of 5-FU44 as well as possibly reducing the frequency of palmar-plantar erythrodysesthesia.18,44-46 In conclusion, tolerability of BOF-A2 seems to be comparable to other oral fluoropyrimidines and shows evidence of antitumor activity as a single agent. Further clinical investigation is indicated.
We thank Ana Petrovich for manuscript preparation and acknowledge Covance Laboratories for their bioanalytical efforts.
The views expressed in this article are the result of independent work and do not represent the views of the United States Food and Drug Administration or the United States Government.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
ex 330 nm and 
; the accumulation ratio (Rac), determined as the ratio of Cmin before the first dose on day 14 to Cmin after the first dose on day 1; and the fraction of the administered dose excreted in urine as the metabolite (fe), expressed as a percentage. 
