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

Donald L. Trump, Merrill J. Egorin, Alan Forrest, James K V Willson, Scot Remick, Kendra D. Tutsch

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Abstract

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 (Css) 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 Css 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 Css 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 Css 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 - e0.122Css), r2 = 0.80. When 5FUra dose was substituted for Css, 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 Css 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 Css, 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 Css 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 Css determined by the risk and severity of toxicity deemed acceptable.

Original languageEnglish (US)
Pages (from-to)2027-2035
Number of pages9
JournalJournal of Clinical Oncology
Volume9
Issue number11
StatePublished - Nov 1991

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Stomatitis
Dipyridamole
Fluorouracil
Pharmacokinetics
Intravenous Infusions

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Trump, D. L., Egorin, M. J., Forrest, A., Willson, J. K. V., Remick, S., & Tutsch, K. D. (1991). Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole. Journal of Clinical Oncology, 9(11), 2027-2035.

Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole. / Trump, Donald L.; Egorin, Merrill J.; Forrest, Alan; Willson, James K V; Remick, Scot; Tutsch, Kendra D.

In: Journal of Clinical Oncology, Vol. 9, No. 11, 11.1991, p. 2027-2035.

Research output: Contribution to journalArticle

Trump, DL, Egorin, MJ, Forrest, A, Willson, JKV, Remick, S & Tutsch, KD 1991, 'Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole', Journal of Clinical Oncology, vol. 9, no. 11, pp. 2027-2035.
Trump, Donald L. ; Egorin, Merrill J. ; Forrest, Alan ; Willson, James K V ; Remick, Scot ; Tutsch, Kendra D. / Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole. In: Journal of Clinical Oncology. 1991 ; Vol. 9, No. 11. pp. 2027-2035.
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abstract = "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 (Css) 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 Css 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 Css 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 Css 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 - e0.122Css), r2 = 0.80. When 5FUra dose was substituted for Css, 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 Css 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 Css, 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 Css 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 Css determined by the risk and severity of toxicity deemed acceptable.",
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N2 - 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 (Css) 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 Css 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 Css 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 Css 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 - e0.122Css), r2 = 0.80. When 5FUra dose was substituted for Css, 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 Css 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 Css, 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 Css 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 Css determined by the risk and severity of toxicity deemed acceptable.

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