A study to evaluate the pharmacokinetics of oral 5-fluorouracil and eniluracil after concurrent administration to patients with refractory solid tumours and varying degrees of renal impairment (FUMA1005)

Eniluracil is an inactivator of dihydropyrimidine dehydrogenase, the first enzyme in the catabolic pathway of 5-fluorouracil (5-FU). Concurrent administration of oral eniluracil with oral 5-FU not only increases the bioavailability of 5-FU, owing to elimination of first-pass metabolism, but can change the route of elimination of 5-FU from hepatic metabolism to renal excretion. An open-label study was performed to determine the effect of renal impairment on the pharmacokinetics of 5-FU in the presence of eniluracil. Enrolled in the study were 17 patients with refractory solid tumours (Karnofsky performance status >/=70%; age 31-74 years; 12 male, 5 female). The patients were separated into two groups based upon creatinine clearance (CLCr): group A had "normal" renal function arbitrarily defined as CLCr >/=50 ml/min ( n=8), and group B had moderate renal impairment, i.e. CLCr <50 ml/min ( n=9). Treatment was separated into test and treatment periods. During the test period all patients received eniluracil 50 mg orally on days 1-3 and 5-FU 10 mg/m(2) together with pharmacokinetic measurements. During the treatment period, all patients received eniluracil 50 mg orally on days 1-7 with 5-FU at a standard dose of 20 mg/m(2) for those in group A or a dose individualized according to the pharmacokinetic parameters in the test period for those in group B. The clearance of both eniluracil and 5-FU was decreased in patients with renal impairment compared to those with normal renal function. A linear relationship was observed between 5-FU CL/F and CLCr in patients with renal impairment, but not in those with normal renal function. 5-FU dose modification, on the basis of the test dose pharmacokinetic data for the patients with renal function impairment, accurately resulted in drug exposure in the potentially therapeutic range. Toxicity was not increased. Eniluracil increases the oral bioavailability of 5-FU and results in a switch from hepatic metabolism to renal elimination. A standard dose of this combination can be administered safely to patients with CLCr >50 ml/min. The combination can also be given to patients with renal impairment using a test dose and pharmacokinetic measurements to predict the appropriate dose of 5-FU. It is expected that sufficient information will be available from this and other studies to allow accurate prediction of the appropriate 5-FU dose modifications required in patients with renal impairment