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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)647-653
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume62
Issue number4
DOIs
StatePublished - Sep 2008
Externally publishedYes

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gemcitabine
Pharmacokinetics
Pancreas
Adenocarcinoma
Toxicity
Plasmas
Ascitic Fluid
Dialysis Solutions
Area Under Curve
Fluids
Therapeutics
Incidence
Metabolites
Drug-Related Side Effects and Adverse Reactions
Pancreatic Neoplasms
Ascites
Pharmaceutical Preparations
High Pressure Liquid Chromatography
Glucose
Drug Therapy

Keywords

  • Gemcitabine
  • Intraperitoneal chemotherapy
  • Pancreatic cancer
  • Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Gamblin, T. C., Egorin, M. J., Zuhowski, E. G., Lagattuta, T. F., Herscher, L. L., Russo, A., ... Bartlett, D. L. (2008). Intraperitoneal gemcitabine pharmacokinetics: A pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas. Cancer Chemotherapy and Pharmacology, 62(4), 647-653. https://doi.org/10.1007/s00280-007-0647-9

Intraperitoneal gemcitabine pharmacokinetics : A pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas. / Gamblin, T. Clark; Egorin, Merrill J.; Zuhowski, Eleanor G.; Lagattuta, Theodore F.; Herscher, Laurie L.; Russo, Angelo; Libutti, Steven K.; Alexander, H. Richard; Dedrick, Robert L.; Bartlett, David L.

In: Cancer Chemotherapy and Pharmacology, Vol. 62, No. 4, 09.2008, p. 647-653.

Research output: Contribution to journalArticle

Gamblin, TC, Egorin, MJ, Zuhowski, EG, Lagattuta, TF, Herscher, LL, Russo, A, Libutti, SK, Alexander, HR, Dedrick, RL & Bartlett, DL 2008, 'Intraperitoneal gemcitabine pharmacokinetics: A pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas', Cancer Chemotherapy and Pharmacology, vol. 62, no. 4, pp. 647-653. https://doi.org/10.1007/s00280-007-0647-9
Gamblin, T. Clark ; Egorin, Merrill J. ; Zuhowski, Eleanor G. ; Lagattuta, Theodore F. ; Herscher, Laurie L. ; Russo, Angelo ; Libutti, Steven K. ; Alexander, H. Richard ; Dedrick, Robert L. ; Bartlett, David L. / Intraperitoneal gemcitabine pharmacokinetics : A pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas. In: Cancer Chemotherapy and Pharmacology. 2008 ; Vol. 62, No. 4. pp. 647-653.
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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 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.",
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T1 - Intraperitoneal gemcitabine pharmacokinetics

T2 - A pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas

AU - Gamblin, T. Clark

AU - Egorin, Merrill J.

AU - Zuhowski, Eleanor G.

AU - Lagattuta, Theodore F.

AU - Herscher, Laurie L.

AU - Russo, Angelo

AU - Libutti, Steven K.

AU - Alexander, H. Richard

AU - Dedrick, Robert L.

AU - Bartlett, David L.

PY - 2008/9

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N2 - 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 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.

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KW - Intraperitoneal chemotherapy

KW - Pancreatic cancer

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