Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon Alfa-2b in patients with advanced cancer

Lynn L. Danhauser, Jack H. Freimann, Tracy L. Gilchrist, Jordan U. Gutterman, Carol Y. Hunter, Anita C. Yeomans, Avi Markowitz

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    Abstract

    Purpose: Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated. Portents and Methods: FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 × 106 U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography. Results: The maximum-tolerated dose of rIFN-a was 10 × 106 U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Casi; range, 0.77 ± 0.35 μmol/L to 1.85 ± 0.48 μmol/L), elimination half-life (t1/2; mean, 9.7 ± 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 μmol/L × hours), total-body clearance (Cl; range, 1,172 to 3,236 ml/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 μmol/l.) was greater than that before rIFN-a administration (1.02 μmol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20% to 35% compared with use of FUra alone (P < .0001). Patients with a greater than 20% decrease in FUra Cl had a fourfold greater incidence of diarrhea. Conclusion: rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted.

    Original languageEnglish (US)
    Pages (from-to)751-761
    Number of pages11
    JournalJournal of Clinical Oncology
    Volume11
    Issue number4
    StatePublished - 1993

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    interferon alfa-2b
    Fluorouracil
    Pharmacokinetics
    Neoplasms

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Danhauser, L. L., Freimann, J. H., Gilchrist, T. L., Gutterman, J. U., Hunter, C. Y., Yeomans, A. C., & Markowitz, A. (1993). Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon Alfa-2b in patients with advanced cancer. Journal of Clinical Oncology, 11(4), 751-761.

    Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon Alfa-2b in patients with advanced cancer. / Danhauser, Lynn L.; Freimann, Jack H.; Gilchrist, Tracy L.; Gutterman, Jordan U.; Hunter, Carol Y.; Yeomans, Anita C.; Markowitz, Avi.

    In: Journal of Clinical Oncology, Vol. 11, No. 4, 1993, p. 751-761.

    Research output: Contribution to journalArticle

    Danhauser, LL, Freimann, JH, Gilchrist, TL, Gutterman, JU, Hunter, CY, Yeomans, AC & Markowitz, A 1993, 'Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon Alfa-2b in patients with advanced cancer', Journal of Clinical Oncology, vol. 11, no. 4, pp. 751-761.
    Danhauser, Lynn L. ; Freimann, Jack H. ; Gilchrist, Tracy L. ; Gutterman, Jordan U. ; Hunter, Carol Y. ; Yeomans, Anita C. ; Markowitz, Avi. / Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon Alfa-2b in patients with advanced cancer. In: Journal of Clinical Oncology. 1993 ; Vol. 11, No. 4. pp. 751-761.
    @article{6208e984968c46d995fa3c5156355a5a,
    title = "Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon Alfa-2b in patients with advanced cancer",
    abstract = "Purpose: Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated. Portents and Methods: FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 × 106 U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography. Results: The maximum-tolerated dose of rIFN-a was 10 × 106 U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Casi; range, 0.77 ± 0.35 μmol/L to 1.85 ± 0.48 μmol/L), elimination half-life (t1/2; mean, 9.7 ± 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 μmol/L × hours), total-body clearance (Cl; range, 1,172 to 3,236 ml/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 μmol/l.) was greater than that before rIFN-a administration (1.02 μmol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20{\%} to 35{\%} compared with use of FUra alone (P < .0001). Patients with a greater than 20{\%} decrease in FUra Cl had a fourfold greater incidence of diarrhea. Conclusion: rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted.",
    author = "Danhauser, {Lynn L.} and Freimann, {Jack H.} and Gilchrist, {Tracy L.} and Gutterman, {Jordan U.} and Hunter, {Carol Y.} and Yeomans, {Anita C.} and Avi Markowitz",
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    T1 - Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon Alfa-2b in patients with advanced cancer

    AU - Danhauser, Lynn L.

    AU - Freimann, Jack H.

    AU - Gilchrist, Tracy L.

    AU - Gutterman, Jordan U.

    AU - Hunter, Carol Y.

    AU - Yeomans, Anita C.

    AU - Markowitz, Avi

    PY - 1993

    Y1 - 1993

    N2 - Purpose: Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated. Portents and Methods: FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 × 106 U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography. Results: The maximum-tolerated dose of rIFN-a was 10 × 106 U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Casi; range, 0.77 ± 0.35 μmol/L to 1.85 ± 0.48 μmol/L), elimination half-life (t1/2; mean, 9.7 ± 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 μmol/L × hours), total-body clearance (Cl; range, 1,172 to 3,236 ml/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 μmol/l.) was greater than that before rIFN-a administration (1.02 μmol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20% to 35% compared with use of FUra alone (P < .0001). Patients with a greater than 20% decrease in FUra Cl had a fourfold greater incidence of diarrhea. Conclusion: rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted.

    AB - Purpose: Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated. Portents and Methods: FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 × 106 U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography. Results: The maximum-tolerated dose of rIFN-a was 10 × 106 U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Casi; range, 0.77 ± 0.35 μmol/L to 1.85 ± 0.48 μmol/L), elimination half-life (t1/2; mean, 9.7 ± 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 μmol/L × hours), total-body clearance (Cl; range, 1,172 to 3,236 ml/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 μmol/l.) was greater than that before rIFN-a administration (1.02 μmol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20% to 35% compared with use of FUra alone (P < .0001). Patients with a greater than 20% decrease in FUra Cl had a fourfold greater incidence of diarrhea. Conclusion: rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted.

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