PHASE-I CLINICAL AND PHARMACOLOGICAL STUDIES OF BENZYLACYCLOURIDINE, A URIDINE PHOSPHORYLASE INHIBITOR

Benzylacyclouridine (BAU, IND 039655) is a potent and specific inhibit or of uridine phosphorylase (UrdPase; EC 2.4.2.3). This enzyme plays a major role in regulating uridine homeostasis and also catalyzes the c onversion of fluoropyrimidine nucleosides to their respective bases. I nhibition of UrdPase enzyme activity 18-24 h after 5-fluorouracil (5-F U) administration increased plasma levels of uridine and enhanced the therapeutic index of 5-FU by rescuing normal tissues. Moreover, in vit ro preclinical studies have also shown that inhibiting UrdPase enzyme activity by BAU prior to administration of 5-FU increased cytotoxicity in a number of human cancer cell lines. A series of preclinical studi es was performed in dogs and pigs to evaluate the pharmacological and pharmacodynamic properties of BAU, These data showed a sustained eleva tion in plasma uridine concentration in both animal models. The rapid degradation of a tracer dose of uridine into uracil was virtually arre sted by BAU administered both p.o. or i.v. The t(1/2), of BAU was 1.8- 3.6 h in dogs, with bioavailability levels of 85% (30 mg/kg) and 42.5% (120 mg/kg), In pigs, the half-life varied from 1.6 to 2.3 h, with a bioavailability of 40% at 120 mg/kg, The drug was distributed into mos t tissues with a tissue: plasma ratio of approximately 0.7. On the bas is of these preclinical studies, we performed a Phase I clinical trial of BAU in patients with advanced cancer. Patients received 200, 400, 800, and 1600 mg/m(2) BAU as a single oral dose. Toxicities included g rade 2 anemia, grade 1 fever, grade 1 fatigue, grade 1 constipation, a nd grade 1 elevation in alkaline phosphatase; none of these toxicities were observed to be dose dependent. The maximum tolerated dose and do se-limiting toxicity were not reached at the doses given. BAU plasma c oncentrations and area under the curve correlated linearly with the or al dose level, The pharmacokinetics of BAU were consistent with a firs t-order clearance, with average peak concentrations ranging from 19 mu M (200 mg/m(2)) to 99 mu M (1600 mg/m(2)) and t(beta 1/2), ranging fr om 3.0 to 3.9 h at the four dose levels, Compared with baseline plasma uridine, treatment of patients with 200, 400, 800, and 1600 mg/m(2) B AU increased peak uridine concentrations by 120, 150, 250, and 175%, r espectively. On the basis of this clinical study, the suggested Phase II starting dose of BAU in combination with 5-FU is 800 mg/m(2). Studi es combining BAU with 5-FU and incorporating appropriate molecular and biochemical end points to assess the effects of this drug combination on tumor and/or surrogate tumor tissue are under way.