Phase I and pharmacologic study of PN401 and fluorouracil in patients with advanced solid malignancies.

Abstract

PURPOSE:

To assess the feasibility of administering PN401, an oral uridine prodrug, as a rescue agent for the toxic effects of fluorouracil (5-FU), and to determine the maximum-tolerated dose of 5-FU when given with PN401, with an 8-hour treatment interval between these agents.

PATIENTS AND METHODS:

Patients with advanced solid malignancies were treated with escalating doses of 5-FU, given as a rapid intravenous infusion weekly for 3 consecutive weeks every 4 weeks. PN401 was administered orally 8 hours after 5-FU administration, to achieve sustained plasma uridine concentrations of at least 50 micromol/L. Initially, patients received 6 g of PN401 orally every 8 hours for eight doses (schedule 1). When dose-limiting toxicity (DLT) was consistently noted, patients then received 6 g of PN401 every 2 hours for three doses and every 6 hours thereafter for 15 doses (schedule 2).

RESULTS:

Twenty-three patients received 50 courses of 5-FU and PN401. Among patients on schedule 1, DLT (grade 4 neutropenia complicated by fever and diarrhea) occurred in those receiving 5-FU 1,250 mg/m(2)/wk. Among patients on schedule 2, 5-FU 1,250 mg/m(2)/wk was well tolerated, but grade 4, protracted (> 5 days) neutropenia was consistently noted in those treated with higher doses of the drugs. Nonhematologic effects were uncommon and rarely severe. The pharmacokinetics of 5-FU, assessed in 12 patients on schedule 2, were nonlinear, with the mean area under the time-versus-concentration curve (AUC) increasing from 298 +/- 44 to 962 +/- 23 micromol/L and mean clearance decreasing from 34 +/- 4 to 15.6 +/- 0.38 L/h/m(2) as the dose of 5-FU was increased from 1,250 to 1,950 mg/m(2)/wk. 5-FU AUCs achieved with 5-FU 1,250 mg/m(2)/wk for 6 weeks along with the intensified PN401 dose schedule were approximately five-fold higher than those achieved with 5-FU alone. Plasma uridine concentrations increased with each of the three PN401 doses given every 2 hours, and uridine steady-state concentrations were greater than 50 micromol/L.

CONCLUSION:

Treatment with oral PN401 beginning 8 hours after 5-FU administration is well tolerated and results in sustained plasma uridine concentrations above therapeutic-relevant levels. The recommended 5-FU dosage for phase II evaluations is 1,250 mg/m(2)/wk for 3 weeks every 4 weeks with the intensified PN401 dose schedule (schedule 2). At this dose, systemic exposure to 5-FU as measured by AUC was five-fold higher than that observed after administration of a conventional 5-FU bolus.

• Authors: M Hidalgo, M A Villalona-Calero, S G Eckhardt, R L Drengler, G Rodriguez, L A Hammond, S G Diab, G Weiss, A M Garner, E Campbell, K Davidson, A Louie, J D O'Neil, R von Borstel, D D Von Hoff, E K Rowinsky
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 18 Issue 1 Pg. 167-77 (Jan 2000) ISSN: 0732-183X [Print] United States
• PMID: 10623707 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acetates
• Antimetabolites, Antineoplastic
• Prodrugs
• uridine triacetate
• Fluorouracil
• Uridine

Topics

• Acetates
• Adult
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects, pharmacokinetics)
• Cytoprotection
• Diarrhea (chemically induced, prevention & control)
• Dose-Response Relationship, Drug
• Female
• Fluorouracil (administration & dosage, adverse effects, pharmacokinetics)
• Hematologic Diseases (chemically induced, prevention & control)
• Humans
• Male
• Maximum Tolerated Dose
• Neutropenia (chemically induced, prevention & control)
• Prodrugs (chemistry, pharmacokinetics, therapeutic use)
• Statistics, Nonparametric
• Uridine (analogs & derivatives, chemistry, pharmacokinetics, therapeutic use)