Questions About Gemcitabine Dose Rate: Answered or Unanswered?

Abstract

Even before 2 ,2 -difluorodeoxycytidine (dFdC) was given the name gemcitabine, laboratory studies were investigating the biochemical feature of its phosphorylation to demonstrate that the rate of accumulation of its triphosphate (dFdCTP, gemcitabine triphosphate) was saturated by 10 to 20 mol/L of exogenous gemcitabine. The first investigation that established the saturability for gemcitabine triphosphate accumulation was done in a cell line. This was extended to primary cells in vitro and in peripheralblood mononuclear cells (PBMCs) during therapy. In the clinic, when gemcitabine was administered at different doses during a standard 30-minute infusion, the rate of intracellular accumulation of gemcitabine triphosphate was highest when plasma gemcitabine was about 20 mol/L. Pharmacokinetic studies during therapy further established that such gemcitabine levels (20 mol/L) were achieved in plasma with a dose rate of 10 mg/m/ min, hence coining the term fixed dose rate (FDR) of gemcitabine. At this dose rate, a continuous increase in gemcitabine triphosphate concentration was observed for up to 18 hours. For the FDR delivery, generally 1,000 or 1,500 mg/m is infused during 100 or 150 minutes, respectively. In contrast, a phase I dose escalation trial established that the maximum tolerated dose of gemcitabine was 2,200 mg/m/wk for 3 weeks when administered as a 30-minute infusion. This half-hour administration has been the most used schedule and has been termed the standard (STD) dose schedule of gemcitabine. Saturation kinetics that led to a defined dose rate have been observed for cytarabine, a prototype of nucleoside analogs. The reason that phosphorylated moieties of cytarabine (cytarabine triphosphate) and gemcitabine (gemcitabine diphosphate, gemcitabine triphosphate) are the active and cytotoxic metabolites of these nucleoside analogs further underscored the importance of the dose rate of infusion during clinical trials. Although several clinical trials have been performed with gemcitabine, either with STD doses or with FDR schedules, only a few were designed to ask two specific questions: First, is there a greater accumulation of gemcitabine triphosphate with a FDR of gemcitabine; and, second, does this result in a better clinical outcome (Table 1).