Toxicology and pharmacokinetics of intravesical gemcitabine: A preclinicalstudy in dogs

More active and well-tolerated agents are needed for the treatment of super ficial bladder cancer. This study investigated intravesical gemcitabine to establish the toxicology and pharmacokinetics necessary for clinical trials . Beagle dogs tin groups of 2; n = 6) received 100 mg, 350 mg, or 1 g of dr ug by intravesical administration on alternate days three times/week for 4 weeks. Animals were observed for clinical signs of toxicity; gemcitabine le vels and peripheral blood counts were taken three times weekly. The dogs we re euthanized, and a full necropsy was performed at days 1 and 14 after the last dose. Intravesical gemcitabine was given at 100 mg (n = 2), 350 mg (e quivalent to the 1000 mg/m(2) human dose; n = 3), and 3.5 g (n = 1), i.v. g emcitabine was given at 350 mg (n = 2), Plasma samples drawn at time points up to 8 h were analyzed for systemic absorption and clearance of drug. Dos es of 100 and 350 mg were well tolerated with no clinical side effects. Nec ropsies revealed normal bone marrow cellularity and normal bladder histolog y, At 1 g, signs of severe clinical toxicity were evident, and after only t hree doses, necropsies demonstrated severe bone marrow hypoplasia, cystitis , and intestinal necrosis, At all intravesical doses, significant systemic absorption was seen, The T-1/2 (+/-SD) for intravesical and i.v. administra tion of 350 mg was 328 (+/-6.8) min and 99.3 (+/-5.2) min, respectively (P < 0.001). Intravesical gemcitabine is well tolerated and has no direct blad der toxicity at doses up to 1000 mg/m(2). Higher doses result in gastrointe stinal, bladder, and bone marrow toxicity.