Phase I trial of PN401, an oral prodrug of uridine, to prevent toxicity from fluorouracil in patients with advanced cancer

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
David P KelsenJ Bertino

Abstract

We performed a phase I study to determine the appropriate dose of PN401, a uridine (URD) prodrug, to use as a rescue agent for fluorouracil (FU) and than to determine the maximum-tolerated dose (MTD) of FU when given with PN401. Patients with advanced cancer received oral PN401 as either a suspension or a tablet in escalating doses. A pharmacokinetic analysis was performed to determine which dose best achieved a target value of sustained levels of URD > or = 50 mumol/L. In the first phase of the study, all patients received a fixed dose of FU 600 mg/m2 as a rapid intravenous bolus followed by 10 doses of PN401 given at 6-hour intervals. PN401 therapy commenced 24 hours after FU. After determination of the appropriate dose of PN401, a second group of patients received escalating doses of FU with a fixed dose of PN401. Thirty-eight patients with advanced cancer received PN401 and FU. Pharmacokinetic analysis indicated that either 6.6 g of PN401 as an oral suspension or 6 g given in tablet form resulted in high bioavailability of URD, with sustained plasma concentrations greater than 50 mumol/L. In the second phase of the study, FU doses were escalated from 600 to 1,000 mg/m2. FU was given as a rapid intravenous bolus weekly for 6...Continue Reading

Citations

Dec 14, 2006·Cancer Chemotherapy and Pharmacology·M W SaifRobert B Diasio
Jan 7, 2000·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M HidalgoE K Rowinsky
Sep 28, 2005·Cancer Chemotherapy and Pharmacology·Muhammad Wasif Saif, Reid von Borstel
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Aug 31, 2020·Protein Science : a Publication of the Protein Society·Yu-Ting HuangPei-Fen Liu
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Jun 27, 2002·Biochimica Et Biophysica Acta·Giuseppe PizzornoRobert E Handschumacher

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