This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grimison, P. Articles by Links, M. J. Search for Related Content PubMed PubMed Citation Articles by Grimison, P. Articles by Links, M. J. Related Articles Related Editorial

Randomized Crossover Study Evaluating the Effect of Gemcitabine Infusion Dose Rate: Evidence of Auto-Induction of Gemcitabine Accumulation

Peter Grimison, Peter Galettis, Susan Manners, Maria Jelinek, Ekkaphon Metharom, Paul L. de Souza, Winston Liauw, Matthew J. Links

From the Cancer Pharmacology Therapeutics Group, St George and Sutherland Hospitals; the University of New South Wales; and the Clinical Trials Unit, St George Hospital Cancer Care Centre, Sydney, Australia

Address reprint requests to Peter Galettis, PhD, Cancer Care Centre, St George Hospital, Gray St, Kogarah, NSW 2217, Australia; e-mail: Peter.Galettis{at}sesiahs.health.nsw.gov.au or p.galettis{at}unsw.edu.au

Purpose: Controversy exists over the optimal dose rate for administration of gemcitabine. There is a strong pharmacologic rationale for increased intracellular accumulation with prolonged infusions, but this failed to translate into a significant benefit in a large randomized study. The purpose of this study was to compare the intracellular pharmacokinetics of gemcitabine given for 30 minutes or for 100 minutes in a crossover design.

Patients and Methods: We randomly assigned 33 patients to a standard dose of 1,000 mg/m² over either 30 minutes or 100 minutes. At the second week, they were transferred to the alternate schedule. Blood samples were collected at various times after the gemcitabine infusion. Gemcitabine and difluorodeoxyuridine were measured in plasma by high-performance liquid chromatography (HPLC), and gemcitabine-triphosphate was measured by HPLC in leukocytes.

Results: Intracellular accumulation was greater during the 100-minute infusion, which was consistent with previous data. This effect was confounded by an increase in gemcitabine-triphosphate accumulation between weeks 1 and 2, which was consistent with self-induction of gemcitabine accumulation. There was significant heterogeneity: 27% of patients had greater WBC accumulation during the 30-minute infusion (regardless of treatment order). Patients with relatively greater levels of gemcitabine-triphosphate in WBCs tended to have less under-dosing and a greater reduction in midcycle neutrophils. However, this observation did not correlate with plasma gemcitabine levels.

Conclusion: This work identifies significant variations in intracellular gemcitabine-triphosphate accumulation between and within individuals, and it provides evidence that this variation has potential clinical significance. The observed self-induction of gemcitabine metabolism has broad implications for the dosing of nucleoside analogs.

This study was supported by a research grant from Eli Lilly Australia.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Related Editorial

• Questions About Gemcitabine Dose Rate: Answered or Unanswered?
  Varsha Gandhi
  JCO 2007 25: 5691-5694 [Full Text]

This article has been cited by other articles:

				J. H. Beumer, J. L. Eiseman, R. A. Parise, E. Joseph, J. M. Covey, and M. J. Egorin Modulation of Gemcitabine (2',2'-Difluoro-2'-Deoxycytidine) Pharmacokinetics, Metabolism, and Bioavailability in Mice by 3,4,5,6-Tetrahydrouridine Clin. Cancer Res., June 1, 2008; 14(11): 3529 - 3535. [Abstract] [Full Text] [PDF]

				K. Miyanishi, H. Ishiwatari, T. Hayashi, M. Takahashi, Y. Kawano, K. Takada, H. Ihara, T. Okuda, K. Takanashi, S. Takahashi, et al. A Phase I Trial of Arterial Infusion Chemotherapy with Gemcitabine and 5-Fluorouracil for Unresectable Advanced Pancreatic Cancer after Vascular Supply Distribution via Superselective Embolization Jpn. J. Clin. Oncol., April 1, 2008; 38(4): 268 - 274. [Abstract] [Full Text] [PDF]

				V. Gandhi Questions About Gemcitabine Dose Rate: Answered or Unanswered? J. Clin. Oncol., December 20, 2007; 25(36): 5691 - 5694. [Full Text] [PDF]