Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase

S. D. Baker, S. P. Khor, Alex Adjei, M. Doucette, T. Spector, R. C. Donehower, L. B. Grochow, S. E. Sartorius, D. A. Noe, J. A. Hohneker, E. K. Rowinsky

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Abstract

Purpose: To study the absolute bioavailability and pharmacokinetics of an oral solution of fluorouracil (5-FU) in patients treated with 776C85, an oral inactivator of dihydropyrimidine dehydrogenase (DPD), and to evaluate the feasibility of administering oral 5-FU and 776C85 on a multiple-daily dosing schedule. Patients and Methods: Twelve patients with refractory solid tumors were enrolled onto this three-period study. In periods 1 and 2, patients were randomly assigned to treatment with 5-FU 10 mg/m2 on day 2 given by either the oral or intravenous (IV) route with oral 776C85 3.7 mg/m2/d on days 1 and 2. In period 3, patients received escalating doses of 5-FU (10 to 25 mg/m2/d) orally for 5 days (days 2 to 6) with 776C85 3.7 mg/m2/d orally (days 1 to 7) every 4 weeks. Pharmacokinetic studies were performed in periods 1 and 2, and after the fifth oral dose of 5-FU in period 3. Results: Twelve patients completed the bioavailability and pharmacokinetic studies. Following oral 5-FU 10 mg/m2, the bioavailability was 122% ± 40% (mean ± SD), the terminal half-life (t(1/2β)) was 4.5 ± 1.6 hours, the apparent volume of distribution (Vβ) was 21.4 ± 5.9 L/m2, and the systemic clearance (Cl(sys)) was 57.6 ± 16.4 mL/min/m2. A correlation was observed between oral 5-FU systemic clearance and calculated creatinine clearance (r = .74; P = .009). Multiple-daily dosing did not appear to affect the pharmacokinetics of oral 5-FU. Neutropenia was the principal toxicity of oral 5-FU and 776C85, precluding escalation of oral 5-FU to doses greater than 25 mg/m2/d for 5 days every 4 weeks with 776C85. Conclusion: The oral DPD inactivator 776C85 enables oral administration of 5-FU and may alter conventional 5-FU administration practices.

Original languageEnglish (US)
Pages (from-to)3085-3096
Number of pages12
JournalJournal of Clinical Oncology
Volume14
Issue number12
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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Dihydrouracil Dehydrogenase (NADP)
Fluorouracil
Biological Availability
Pharmacokinetics
Safety
eniluracil
Neutropenia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. / Baker, S. D.; Khor, S. P.; Adjei, Alex; Doucette, M.; Spector, T.; Donehower, R. C.; Grochow, L. B.; Sartorius, S. E.; Noe, D. A.; Hohneker, J. A.; Rowinsky, E. K.

In: Journal of Clinical Oncology, Vol. 14, No. 12, 01.01.1996, p. 3085-3096.

Research output: Contribution to journalArticle

Baker, SD, Khor, SP, Adjei, A, Doucette, M, Spector, T, Donehower, RC, Grochow, LB, Sartorius, SE, Noe, DA, Hohneker, JA & Rowinsky, EK 1996, 'Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase', Journal of Clinical Oncology, vol. 14, no. 12, pp. 3085-3096. https://doi.org/10.1200/JCO.1996.14.12.3085
Baker, S. D. ; Khor, S. P. ; Adjei, Alex ; Doucette, M. ; Spector, T. ; Donehower, R. C. ; Grochow, L. B. ; Sartorius, S. E. ; Noe, D. A. ; Hohneker, J. A. ; Rowinsky, E. K. / Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. In: Journal of Clinical Oncology. 1996 ; Vol. 14, No. 12. pp. 3085-3096.
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abstract = "Purpose: To study the absolute bioavailability and pharmacokinetics of an oral solution of fluorouracil (5-FU) in patients treated with 776C85, an oral inactivator of dihydropyrimidine dehydrogenase (DPD), and to evaluate the feasibility of administering oral 5-FU and 776C85 on a multiple-daily dosing schedule. Patients and Methods: Twelve patients with refractory solid tumors were enrolled onto this three-period study. In periods 1 and 2, patients were randomly assigned to treatment with 5-FU 10 mg/m2 on day 2 given by either the oral or intravenous (IV) route with oral 776C85 3.7 mg/m2/d on days 1 and 2. In period 3, patients received escalating doses of 5-FU (10 to 25 mg/m2/d) orally for 5 days (days 2 to 6) with 776C85 3.7 mg/m2/d orally (days 1 to 7) every 4 weeks. Pharmacokinetic studies were performed in periods 1 and 2, and after the fifth oral dose of 5-FU in period 3. Results: Twelve patients completed the bioavailability and pharmacokinetic studies. Following oral 5-FU 10 mg/m2, the bioavailability was 122{\%} ± 40{\%} (mean ± SD), the terminal half-life (t(1/2β)) was 4.5 ± 1.6 hours, the apparent volume of distribution (Vβ) was 21.4 ± 5.9 L/m2, and the systemic clearance (Cl(sys)) was 57.6 ± 16.4 mL/min/m2. A correlation was observed between oral 5-FU systemic clearance and calculated creatinine clearance (r = .74; P = .009). Multiple-daily dosing did not appear to affect the pharmacokinetics of oral 5-FU. Neutropenia was the principal toxicity of oral 5-FU and 776C85, precluding escalation of oral 5-FU to doses greater than 25 mg/m2/d for 5 days every 4 weeks with 776C85. Conclusion: The oral DPD inactivator 776C85 enables oral administration of 5-FU and may alter conventional 5-FU administration practices.",
author = "Baker, {S. D.} and Khor, {S. P.} and Alex Adjei and M. Doucette and T. Spector and Donehower, {R. C.} and Grochow, {L. B.} and Sartorius, {S. E.} and Noe, {D. A.} and Hohneker, {J. A.} and Rowinsky, {E. K.}",
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T1 - Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase

AU - Baker, S. D.

AU - Khor, S. P.

AU - Adjei, Alex

AU - Doucette, M.

AU - Spector, T.

AU - Donehower, R. C.

AU - Grochow, L. B.

AU - Sartorius, S. E.

AU - Noe, D. A.

AU - Hohneker, J. A.

AU - Rowinsky, E. K.

PY - 1996/1/1

Y1 - 1996/1/1

N2 - Purpose: To study the absolute bioavailability and pharmacokinetics of an oral solution of fluorouracil (5-FU) in patients treated with 776C85, an oral inactivator of dihydropyrimidine dehydrogenase (DPD), and to evaluate the feasibility of administering oral 5-FU and 776C85 on a multiple-daily dosing schedule. Patients and Methods: Twelve patients with refractory solid tumors were enrolled onto this three-period study. In periods 1 and 2, patients were randomly assigned to treatment with 5-FU 10 mg/m2 on day 2 given by either the oral or intravenous (IV) route with oral 776C85 3.7 mg/m2/d on days 1 and 2. In period 3, patients received escalating doses of 5-FU (10 to 25 mg/m2/d) orally for 5 days (days 2 to 6) with 776C85 3.7 mg/m2/d orally (days 1 to 7) every 4 weeks. Pharmacokinetic studies were performed in periods 1 and 2, and after the fifth oral dose of 5-FU in period 3. Results: Twelve patients completed the bioavailability and pharmacokinetic studies. Following oral 5-FU 10 mg/m2, the bioavailability was 122% ± 40% (mean ± SD), the terminal half-life (t(1/2β)) was 4.5 ± 1.6 hours, the apparent volume of distribution (Vβ) was 21.4 ± 5.9 L/m2, and the systemic clearance (Cl(sys)) was 57.6 ± 16.4 mL/min/m2. A correlation was observed between oral 5-FU systemic clearance and calculated creatinine clearance (r = .74; P = .009). Multiple-daily dosing did not appear to affect the pharmacokinetics of oral 5-FU. Neutropenia was the principal toxicity of oral 5-FU and 776C85, precluding escalation of oral 5-FU to doses greater than 25 mg/m2/d for 5 days every 4 weeks with 776C85. Conclusion: The oral DPD inactivator 776C85 enables oral administration of 5-FU and may alter conventional 5-FU administration practices.

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