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Toceranib phosphate (Palladia, SU11654), a multireceptor tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity, has been developed for the treatment of mast cell tumors in dogs. An overview of the distribution, metabolism, and excretion of toceranib phosphate in dogs is presented. When [(14)C]-toceranib was orally administered to dogs, the majority of the radioactivity (92%) was excreted in feces and only a small portion (7%) was excreted in urine. Seven days after a single 3.25 mg/kg oral dose, radioactivity was the highest in bile and liver, with measurable concentrations in lymph nodes, colon, adrenals, bone marrow, kidneys, lungs, spleen, pancreas, and skin. Plasma protein binding of toceranib in fresh plasma ranged from 90.8% to 92.8% at concentrations between 20 ng/mL and 500 ng/mL and was independent of concentration. Microsomal and hepatocyte incubations resulted in the formation of a single metabolite. Spectrometric analysis of the metabolite was consistent with the formation of an alicyclic N-oxide of toceranib. The combination of the high rate of fecal excretion and the long elimination half-life of toceranib indicate enterohepatic recirculation of the parent compound and/or the N-oxide metabolite.

Yancey, M. F., Merritt, D. A., Lesman, S. P., Boucher, J. F., Michels, G. M. Pharmacokinetic properties of toceranib phosphate (Palladia™, SU11654), a novel tyrosine kinase inhibitor, in laboratory dogs and dogs with mast cell tumors. J. vet. Pharmacol. Therap. 33, 162–171. Toceranib phosphate (Palladia™, SU11654), an oral tyrosine-kinase inhibitor, is under investigation for the treatment of mast cell tumors in dogs. The pharmacokinetics of toceranib phosphate has been characterized in dogs. Means of the following pharmacokinetic parameters were estimated following a 1.0 mg/kg i.v. dose to laboratory beagles: plasma clearance of 1.45 L/kg/h, volume of distribution of 29.7 L/kg, and terminal half-life of 17.7 h. Following single oral doses of 3.25 mg/kg administered to laboratory beagles, mean Cmax estimates ranged from 68.6 ng/mL to 112 ng/mL with tmax ranging from 5.3 h and 9.3 h postdose. Terminal half-life was estimated at 31 h. Oral bioavailability was 76.9%. There were no statistically significant ( P > 0.05) differences with any pharmacokinetic parameter due to fed/fasted state or with time during 13 weeks of every-other-day dosing at 3.25 mg/kg. Toceranib concentrations were proportional with dose over the range of 2.0 to 6.0 mg/kg. The pharmacokinetics of toceranib in client-owned dogs of a variety of pure and mixed breeds with mast cell tumors was similar to that in healthy laboratory dogs. In summary, toceranib phosphate exhibited moderate clearance, a high volume of distribution, and a moderate elimination half-life. After a single oral dose at 3.25 mg/kg, the concentration vs. time curve showed broad, sustained exposure with measurable concentrations for more than 48 h. These pharmacokinetic parameters support every-other-day administration of toceranib phosphate at an initial dose of 3.25 mg/kg for the treatment of mast cell tumors in dogs. [ABSTRACT FROM AUTHOR]