Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 4, pp 647–653

Intraperitoneal gemcitabine pharmacokinetics: a pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas

  • T. Clark Gamblin
  • Merrill J. Egorin
  • Eleanor G. Zuhowski
  • Theodore F. Lagattuta
  • Laurie L. Herscher
  • Angelo Russo
  • Steven K. Libutti
  • H. Richard Alexander
  • Robert L. Dedrick
  • David L. Bartlett
Original Article

Abstract

Background

The pyrimidine analogue gemcitabine (2′, 2′-difluorodeoxycitidine, dFdC) is active against pancreatic cancer, and its high clearance (CLtb) 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/m2 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/m2 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 μg/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 μg/ml) throughout treatment. The mean area under the concentration versus time curve (AUC) for dFdC in peritoneal fluid was 182 μg/ml × h, which was approximately 70× 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 CLtb and low incidence of local toxicity of dFdC and argue for its further evaluation as a drug for IP therapy.

Keywords

Intraperitoneal chemotherapy Pharmacokinetics Gemcitabine Pancreatic cancer 

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • T. Clark Gamblin
    • 1
    • 2
    • 9
  • Merrill J. Egorin
    • 3
    • 4
    • 5
  • Eleanor G. Zuhowski
    • 5
  • Theodore F. Lagattuta
    • 5
  • Laurie L. Herscher
    • 6
  • Angelo Russo
    • 6
  • Steven K. Libutti
    • 7
  • H. Richard Alexander
    • 7
  • Robert L. Dedrick
    • 8
  • David L. Bartlett
    • 2
    • 7
  1. 1.Division of Surgical Oncology, Department of SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Division of Transplantation, Department of SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Division of Hematology/Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of PharmacologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  5. 5.Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  6. 6.Radiation Oncology BranchNational Cancer Institute, National Institutes of HealthBethesdaUSA
  7. 7.Surgery BranchNational Cancer Institute, National Institutes of HealthBethesdaUSA
  8. 8.Division of Bioengineering and Physical Science, Office of Research ServicesNational Institutes of HealthBethesdaUSA
  9. 9.Liver Cancer Center, UPMC Montefiore HospitalPittsburghUSA

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