Pharmacokinetics and bioequivalence of a combined oral formulation of eniluracil, an inactivator of dihydropyrimidine dehydrogenase, and 5-fluorouracil in patients with advanced solid malignancies

Background: This study was performed to evaluate the pharmacokinetics, bioe quivalence, and feasibility of a combined oral formulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc., Research Triangle Park, North Carolina), an inactivator of dihydropyrimidine dehydrogenase (DPD). The rat ionale for developing a combined eniluracil/5-FU formulation oral dosing fo rm is to simplify treatment with these agents, which has been performed usi ng separate dosing forms, and decrease the probability of severe toxicity a nd/or suboptimal therapeutic results caused by inadvertently high or conver sely insufficient 5-FU dosing. Patients and methods: The trial was a randomized, three-way crossover bioeq uivalence study of three oral dosing forms of eniluracil/5-FU tablets in ad ults with solid malignancies. Each period consisted of two days of treatmen t and a five- to seven-day washout phase. Eniluracil at a dose of 20 mg, wh ich results in maximal DPD inactivation, was administered twice daily on th e first day and in the evening on the second day of each of the three treat ments. On the morning of the second day, all patients received a total enil uracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as either separate tablets (treatment A) or combined eniluracil/5-FU tablets in two d ifferent strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of 1 0/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment C)). Th e pharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinary excretion of eniluracil, 5-FU, uracil, and alpha -fluoro-beta -alanine (FBA L), were studied. To determine the bioequivalence of the combined eniluraci l/5-FU dosing forms compared to the separate tablets, an analysis of varian ce on pharmacokinetic parameters reflecting eniluracil and 5-FU exposure wa s performed. Results: Thirty-nine patients with advanced solid malignancies had complete pharmacokinetic studies performed during treatments A, B, and C. The pharm acokinetics of eniluracil and 5-FU were similar among the three types of tr eatment. Both strengths of the combined eniluracil/5-FU dosing form and the separate dosing forms were bioequivalent. Mean values for terminal half-li fe, systemic clearance, and apparent volume of distribution for oral 5-FU d uring treatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and 50.7/51.5/50.0 liters, respectively. The intersubject coefficient of varia tion for pharmacokinetic variables reflecting 5-FU exposure and clearance i n treatments ranged from 23% to 33%. The urinary excretion of unchanged 5-F U over 24 hours following treatments A, B, and C averaged 52.2%, 56.1%, and 50.8% of the administered dose of 5-FU, respectively. Parameters reflectin g DPD inhibition, including plasma uracil and urinary FBAL excretion follow ing treatments A, B, and C were similar. Toxicity was generally mild and si milar following all three types of treatments. Conclusions: The pharmacokinetics of 5-FU and eniluracil were similar and m et bioequivalence criteria following treatment with the separate oral formu lations of 5-FU and eniluracil and two strengths of the combined formulatio n. The availability of a combined eniluracil/5-FU oral dosing form will lik ely simplify dosing and decrease the probability of severe toxicity or subo ptimal therapeutic results caused by an inadvertent 5-FU overdose or insuff icient 5-FU dosing in the case of separate oral formulations, thereby enhan cing the overall feasibility and therapeutic index of oral 5-FU therapy.