title: Phase I and pharmacologic study of PN401 and fluorouracil in patients with advanced solid malignancies.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Institute for Drug Development, Cancer Therapy and Research Center and the University of Texas Health Science Center, San Antonio, TX, USA. mhidalgo@saci.org
authors.forename: M
authors.initials: M
authors.lastname: Hidalgo
authors.forename: M A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: R L
authors.initials: RL
authors.lastname: Drengler
authors.forename: G
authors.initials: G
authors.lastname: Rodriguez
authors.forename: L A
authors.initials: LA
authors.lastname: Hammond
authors.forename: S G
authors.initials: SG
authors.lastname: Diab
authors.forename: G
authors.initials: G
authors.lastname: Weiss
authors.forename: A M
authors.initials: AM
authors.lastname: Garner
authors.forename: E
authors.initials: E
authors.lastname: Campbell
authors.forename: K
authors.initials: K
authors.lastname: Davidson
authors.forename: A
authors.initials: A
authors.lastname: Louie
authors.forename: J D
authors.initials: JD
authors.lastname: O'Neil
authors.forename: R
authors.initials: R
authors.lastname: von Borstel
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000085:Acetates; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D019610:Cytoprotection; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006402:Hematologic Diseases / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018709:Statistics, Nonparametric; D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000085:Acetates; D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; C000609666:uridine triacetate; D005472:Fluorouracil; D014529:Uridine