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

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.