Intraperitoneal gemcitabine pharmacokinetics: a pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas. Cancer Chemother Pharmacol 2008 Sep;62(4):647-53
Date
11/28/2007Pubmed ID
18040687DOI
10.1007/s00280-007-0647-9Scopus ID
2-s2.0-47549100393 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
BACKGROUND: The pyrimidine analogue gemcitabine (2', 2'-difluorodeoxycitidine, dFdC) is active against pancreatic cancer, and its high clearance (CL(tb)) and low incidence of local toxicity make it an excellent candidate for evaluation as intraperitoneal (IP) therapy. We designed a dosing schema that used multiple sequential exchanges of a peritoneal dialysate containing dFdC in an effort to produce prolonged IP dFdC exposure.
METHODS: As part of a study involving multi-modality therapy for advanced pancreatic adenocarcinoma, patients were treated with four 6-h IP dwells of dFdC (50 mg/m(2) in 2 l) over a 24-h period. A second 24-h cycle of IP dFdC therapy was repeated 1 week later. Each exchange of dialysate contained 50 mg/m(2) dFdC in 2 l of commercial 1.5% dextrose dialysis solution. Plasma and peritoneal fluid were analyzed by HPLC to determine concentrations of dFdC and its inactive metabolite 2', 2' difluorodeoxyuridine (dFdU). Clinical data were recorded to note drug toxicity and response.
RESULTS: Nine patients underwent IP dFdC therapy, and eight were able to receive two cycles. There were no recorded significant toxicities. Low plasma dFdC concentrations (<1 microg/ml) were present transiently in seven of nine patients, and dFdC was not detectable in the plasma of the other two. Plasma dFdU concentrations were low but increased gradually until 12 h and then declined little if any. IP dFdC concentrations declined rapidly, and dFdC was seldom measurable prior to administration of the next scheduled 6-h dwell. dFdU concentrations in peritoneal fluid were very low (<0.5 microg/ml) throughout treatment. The mean area under the concentration versus time curve (AUC) for dFdC in peritoneal fluid was 182 microg/ml x h, which was approximately 70x the AUC of dFdC reported in the ascites of a patient undergoing systemic dFdC therapy.
CONCLUSIONS: IP dFdC was well tolerated, and no significant toxicities were noted. The rapid decrease in peritoneal dFdC concentrations and low concentrations of IP dFdU imply almost total absorption of IP-administered dFdC. Little, if any, dFdC could be detected in plasma, but the steady-state plasma dFdU concentrations also imply absorption and inactivation of virtually all IP-administered dFdC. These findings are consistent with the known high CL(tb) and low incidence of local toxicity of dFdC and argue for its further evaluation as a drug for IP therapy.
Author List
Gamblin TC, Egorin MJ, Zuhowski EG, Lagattuta TF, Herscher LL, Russo A, Libutti SK, Alexander HR, Dedrick RL, Bartlett DLAuthor
Thomas Clark Gamblin MD Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenocarcinomaAdult
Antimetabolites, Antineoplastic
Ascitic Fluid
Chromatography, High Pressure Liquid
Combined Modality Therapy
Deoxycytidine
Dialysis Solutions
Female
Humans
Injections, Intraperitoneal
Male
Middle Aged
Pancreatic Neoplasms
Peritoneal Dialysis
Pilot Projects
Survival Rate
