Intraperitoneal gemcitabine pharmacokinetics: a pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas.
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.
Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. gamblintc@upmc.edu
T Clark
TC
Gamblin
Merrill J
MJ
Egorin
Eleanor G
EG
Zuhowski
Theodore F
TF
Lagattuta
Laurie L
LL
Herscher
Angelo
A
Russo
Steven K
SK
Libutti
H Richard
HR
Alexander
Robert L
RL
Dedrick
David L
DL
Bartlett
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001202:Ascitic Fluid / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D015314:Dialysis Solutions / Q000737:chemistry; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D010530:Peritoneal Dialysis; D010865:Pilot Projects; D015996:Survival Rate; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D015314:Dialysis Solutions; D003841:Deoxycytidine; D000093542:Gemcitabine