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Oral Administration of Gemcitabine in Patients with Refractory Tumors: A Clinical and Pharmacologic Study

Authors' Affiliations: ¹ Division of Experimental Therapy and ² Department of Clinical Pharmacology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital; ³ Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, the Netherlands; ⁴ Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; ⁵ Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis; and ⁶ Lilly Research Laboratories, Lilly Research Center, Eli Lilly and Company, Windlesham, United Kingdom

Requests for reprints: Sander Veltkamp, Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. Phone: 31-512-2047; Fax: 31-512-2050; E-mail: s.veltkamp{at}nki.nl.

Purpose: To determine the toxicity, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of oral gemcitabine (2',2'-difluorodeoxycytidine; dFdC) in patients with cancer.

Experimental Design: Patients with advanced or metastatic cancer refractory to standard therapy were eligible. Gemcitabine was administered p.o. starting at 1 mg once daily using dose escalation with three patients per dose level. Patients received one of two dosing schemes: (a) once daily dosing for 14 days of a 21-day cycle or (b) every other day dosing for 21 days of a 28-day cycle. Pharmacokinetics were assessed by measuring concentrations of dFdC and 2',2'-difluorodeoxyuridine (dFdU) in plasma and gemcitabine triphosphate in peripheral blood mononuclear cells, and pharmacodynamics by measuring the effect on T-cell proliferation.

Results: Thirty patients entered the study. Oral gemcitabine was generally well-tolerated. The maximum tolerated dose was not reached. Mainly moderate gastrointestinal toxicities occurred except for one patient who died after experiencing grade 4 hepatic failure during cycle two. One patient with a leiomyosarcoma had stable disease during 2 years and 7 months. Systemic exposure to dFdC was low with an estimated bioavailability of 10%. dFdC was highly converted to dFdU, probably via first pass metabolism and dFdU had a long terminal half-life (89 h). Concentrations of dFdCTP in peripheral blood mononuclear cells were low, but high levels of gemcitabine triphosphate, the phosphorylated metabolite of dFdU, were detected.

Conclusions: Systemic exposure to oral gemcitabine was low due to extensive first-pass metabolism to dFdU. Moderate toxicity combined with hints of activity warrant further investigation of the concept of prolonged exposure to gemcitabine.

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