Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole

During a phase 1 trial of 3-day simultaneous continuous intravenous infusions of varying doses of fluorouracil (5FUra) and 7.7 mg/kg/d of dipyridamole, we examined the relationships between 5FUra dose and steady-state plasma concentration (C_ss) and the percentage reduction in WBCs, as well as the percentage frequency of stomatitis. The SFUra was administered at doses ranging from 185 mg/m²/d times three to 3,600 mg/mVd times three. In 42 patients, 86 cycles of 5FUra plus dipyridamole and 28 cycles of 5FUra alone were analyzed. The C_ss of 5FUra varied even within the same dose level. When patients receiving the same 5FUra dose were considered, the interpatient coefficient of variation of 5FUra C_ss in cycles of 5FUra plus dipyridamole was 23% ± 4.2%. For courses of 5FUra alone, the coefficient of variation of 5FUra was 15.6% ± 6.5%. When the occurrence of any degree of stomatitis was related to the C_ss 5FUra, with patients grouped in cohorts of 2μmol/L increments, the following equations accurately described the frequency of stomatitis: for 5FUra plus dipyridamole, percentage frequency of stomatitis = 100(1 - e ^-0.114Css), r² = 0.88; for 5FUra alone, percentage frequency stomatitis = 100 (1 - e^0.122Css), r² = 0.80. When 5FUra dose was substituted for C_ss, these relationships were as follows: percentage frequency of stomatitis = 100 (1 - e^{-0.00031 [dose]}, r² = 0.85; and percentage frequency of stomatitis = 100 (1 - e^{-0.00051 [dose]}), r² = 0.80. When the relationship between the percentage reduction in WBC and C_ss 5FUra was examined, statistically significant relationships were also apparent: for 5FUra plus dipyridamole, percentage reduction in WBC = 100 (1 - e^-0.085Css), r² = 0.46; for 5FUra alone, percentage reduction in WBC = 100 (1 - e^-0.060Css), r² = 0.61. When 5FUra dose was substituted for C_ss, these relationships were as follows: percentage reduction in WBC = 100 (1 - e^{-0.00023 [dose]} r² = 0.40; percentage reduction in WBC = 100 (1 - e^{-0.00024 [dose]}), r² = 0.65. The relationship between either C_ss 5FUra or dose 5FUra and either stomatitis or myelosuppression were also well described by the modified Hill equation (J Theor Biol 20:171-201, 1968). These analyses indicate that it should be possible to develop therapeutic regimens wherein 5FUra is administered to achieve a targeted C_ss determined by the risk and severity of toxicity deemed acceptable.