Pharmacokinetic properties of toceranib phosphate (Palladia™, SU11654), a novel tyrosine kinase inhibitor, in laboratory dogs and dogs with mast cell tumors

Abstract

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 C(max) estimates ranged from 68.6 ng/mL to 112 ng/mL with t(max) 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.

Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia®) in canine mast cell tumor

“…This lack of apparent cross-resistance to the conventional cytotoxic agents VBL and CCNU suggests that these drugs may remain active in patients with TOC-refractory disease. In dogs, the range of achievable concentrations for TOC in vivo has been reported between 30 nM (Cmin) and 200 nM (Cmax) [19,20]. In the current study, growth inhibition assays were carried out to 1 uM, nearly 5-fold the reported Cmax for TOC.…”

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

“…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].…”

“…Although pharmacokinetic analyses have been performed in both healthy dogs and dogs with cancer as part of the Phase I study and in a small number dogs in the MCT pivotal field study [3,7], there has been no coordinated study of toceranib plasma concentrations when intentionally given at lower than the label dose. Therefore, the purpose of this study was to assess the presumed maximum concentration of drug (Cmax) in dogs with cancer receiving an intended dose of 2.5-2.75 mg/kg of toceranib EOD and to evaluate changes in plasma VEGF concentrations during the course of treatment.…”