Clinical Phase I and Pharmacology Study of Gemcitabine (2', 2'-Difluorodeoxycytidine) Administered in a Two-Weekly Schedule

Abstract Gemcitabine (dFdC) was tested in a Phase I trial at 14 doses (40-5700 mg/m2), administered every 2 weeks as a ½ -h infusion to 52 patients with refractory solid cancer. Gemcitabine and its deaminated metabolite difluorodeoxyuridine (dFdU), measured with HPLC, reached plasma peak levels of 2-3 μM at 40 mg/m2 which increased to 512 μM at 5700 mg/m2. Gemcitabine was eliminated rapidly with a t½β of 2.3-15.8 min in the 40-5700 mg/m2 dose range, with one exception of 38 min at 4500 mg/m2. dFdU was still present at a plateau of ± 20 μM from 4-24 h at doses >960 mg/m2. Up to 3650 mg/m2 linear pharmacokinetics were observed for gemcitabine, while those for dFdU were linear over the whole range. Gemcitabine clearance varied between 1.5-12.6 l/min and was 1.5-fold higher in males than in females (p= 0.024); its volume of distribution was 45.2-248 l. In lymphocytes peak levels of the active metabolite dFdCTP were 100-380 pmol/106 cells in the first course. Apparently a plateau was reached which was confirmed by incubation of white blood cells with increasing gemcitabine concentrations up to 500 μM, reaching a plateau of about 350 pmol/106 cells; in contrast in cancer cells this concentration dependence did not exist and accumulation reached about 1590 pmol/106 cells. In tumors isolated from patients treated with gemcitabine dFdCTP reached about 70 pmol/g wet weight. Gemcitabine itself was eliminated only to a limited extent in the urine, but dFdU was eliminated almost completely in the urine in the first 24 h (51- 92%). In conclusion, dFdC was rapidly eliminated in contrast to dFdU, which was present for at least 18 h, as well as dFdCTP in lymphocytes.