Distribution, metabolism, and excretion of toceranib phosphate (Palladia™, SU11654), a novel tyrosine kinase inhibitor, in dogs

Abstract

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.

Evaluation of the adverse event profile and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose

“…In prior studies the Cmax was determined to be approximately 6–8 hours post drug administration [7,8]. Additionally, a pharmacodynamic study in dogs demonstrated that plasma concentrations of toceranib 8 hours post drug administration ranging from 30 to 180 ng/ml were associated with target modulation in vivo [5].…”

“…Physical examination, routine bloodwork (CBC, biochemistry profile) and blood sampling for assessment of toceranib and VEGF plasma concentrations was performed pretreatment and on days 0, 7, 14 and 30 of treatment. On days 0, 7, and 14, blood was collected at 6 and 8 hours post drug administration to coincide with the predicted toceranib Cmax based on previous studies that had established the time of maximum drug concentration (Tmax) to be 5.3-9.3 hours [7,8]. On day 30, blood sampling was performed at 0, 1, 2, 6, 8, and 12 hours post drug administration to confirm either 6 or 8 hours as the true Cmax.…”

“…Toceranib was quantitated in plasma samples using the method previously described [7,8]. Briefly, 50 μL aliquots of plasma were fortified with an internal standard (IS), a deuterated toceranib analog.…”

“…Based on work performed in laboratory dogs as well as pharmacokinetic sampling from dogs in the Phase I study [3,7,8], 3.25 mg/kg of toceranib given EOD provides sustained plasma drug concentrations at or above 40 ng/ml, the presumed necessary threshold for receptor inhibition in vivo as established in rodent studies [4]. Furthermore, in a pharmacodynamic study performed in dogs with MCT, a dose of 3.25 mg/kg of toceranib was found to produce plasma concentrations of drug at 8 hours post administration ranging from 30–180 ng/ml [5].…”

<strong>Kabachnik&ndash;Fields synthesis of novel 2-oxoindolin methyl phosphonate derivatives using CAN.</strong>

“…These compounds inhibit cancer cell proliferation and tumor growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, P glycoprotein, protein kinases and phosphatases [14]. Isatin-based hydrazones have been identified as inhibitors of the protein tyrosine phosphatase Shp2, which plays an important role in cell signaling, cell proliferation, differentiation and migration [15].The marketed anticancer drug Sunitinib [16] and Oratinib contains 2-oxoindolin-3-ylidene moiety where as Ilmofosin and Edelfosin contains phosphonate moiety and a recently marketed anticancer drug, Toceranib phosphate [17] contains 2-oxoindol-3-ylidene as well as phosphonates moiety. Considering the 3 biological importance of 2-oxoindolin-3-ylidene and α-aminophosphonates prompted us to synthesize coupled derivatives containing isatin based hydrazone and α-aminophosphonates with the hope to get novel hybrid derivatives.…”