Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver.
OBJECTIVE
Although oral fluoropyrimidine prodrugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers.


METHODS
Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m2) OGT 719.


RESULTS
Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated.


CONCLUSIONS
The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.
Sharma
R A
RA
University Department of Oncology, Leicester Royal Infirmary, UK. ras20@le.ac.uk
Eatock
M M
MM
Twelves
C J
CJ
Brown
G
G
McLelland
H R
HR
Clayton
K T
KT
O'Byrne
K J
KJ
Moyses
C
C
Carmichael
J
J
Steward
W P
WP
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004334:Drug Administration Schedule; D005260:Female; D005452:Fluoresceins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000031:analogs & derivatives*; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D005452:Fluoresceins; C118197:OGT 719; D005472:Fluorouracil