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

Abstract

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 onT-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 (f89 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.

Pharmacogenomics of Gemcitabine Metabolism: Functional Analysis of Genetic Variants in Cytidine Deaminase and Deoxycytidine Kinase

“…The slope of the initial linear formation rate was used to determine the Cl int since there was a linear relationship between dFdUMP formation by DCK and dFdU concentration. The high dFdUMP concentrations previously reported (Veltkamp et al, 2008) either were formed through direct phosphorylation of dFdU by another kinase, or resulted from the biotransformation of dFdCMP to dFdUMP by deoxycytidine monophosphate deaminase (Mini et al, 2006). As a result, no further studies were conducted on the effects of other DCK variants in the conversion from dFdU to dFdUMP.…”

“…Cells lacking DCK activity are resistant to the dFdC cytotoxicity (Mini et al, 2006). Additionally, dFdU was reported to form dFdU monophosphate (dFdUMP) via direct phosphorylation (Veltkamp et al, 2008), but it is unknown whether DCK is involved (Supplemental Fig. 1).…”

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

“…Oral administration would permit gemcitabine to be given on a more frequent basis that may further enhance efficacy. Clinical studies of the oral availability of gemcitabine found low systemic exposure due to rapid first pass metabolism to dFdU and gastrointestinal toxicity (7,8).…”

Phase I Study of Oral Gemcitabine Prodrug (LY2334737) Alone and in Combination with Erlotinib in Patients with Advanced Solid Tumors

“…In view of this, daily and every other day oral administration of gemcitabine was studied in a previous clinical trial (12). The pharmacokinetic data obtained in this trial revealed that this approach was not feasible because of lack of bioavailability.…”