ATCvet code: QL01EX90

Toceranib is a small molecule, multi-kinase inhibitor, that has both direct anti-tumour and anti-angiogenic activity. Toceranib selectively inhibits the tyrosine kinase activity of several members of the split kinase receptor tyrosine kinase (RTK) family some of which are implicated in tumour growth, pathologic angiogenesis, and metastatic progression of cancer. Toceranib inhibited the activity of Flk-1/KDR tyrosine kinase (vascular endothelial growth factor receptor, VEGFR2), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor (c-Kit) in both biochemical and cellular assays. Toceranib exerts an antiproliferative effect on endothelial cells in‑vitro. Toceranib induces cell cycle arrest and subsequent apoptosis in tumour cell lines expressing activating mutations in the split kinase RTK, c-Kit. Canine mast cell tumour growth is frequently driven by an activating mutation in c-Kit.

The efficacy and safety of Palladia oral tablets for the treatment of mast cell tumours was evaluated in a randomised, placebo-controlled, double-masked, multicentre clinical field study involving 151 dogs with Patnaik grade II or III, recurrent, cutaneous mast cell tumours with/without local lymph node involvement. The field study comprised a 6-week double-blind placebo-controlled phase followed by an un-blinded phase where all dogs received Palladia for a mean duration of 144 days.

Palladia-treated dogs had a significantly greater objective response rate (37.2 %) compared to dogs treated with placebo (7.9 %). After 6 weeks of treatment, a complete response was noted for 8.1 % and partial response was noted for 29.1 % of dogs treated with Palladia. There was also a significant advantage of Palladia over placebo in the secondary efficacy endpoint, time to tumour progression. Median TTP for Palladia treated dogs was 9 to 10 weeks and for placebo-treated dogs it was 3 weeks.

Dogs carrying wild-type c-kit and dogs carrying mutated c-kit responded significantly better to treatment as compared to placebo.

With a regimen of 3.25 mg toceranib/kg bodyweight administered by tablet orally every other day for 2 weeks (7 doses), the following pharmacokinetic parameters of toceranib in plasma in healthy Beagle dogs were reported: elimination half-life (t1/2) 17.2 ± 3.9 hours, time to maximum plasma concentration (Tmax) approximately 6.2 ± 2.6 hours, maximum plasma concentration (Cmax) approximately 108 ± 41 ng/ml, minimum plasma concentration (Cmin) 18.7 ± 8.3 ng/ml and the area under the plasma concentration time-curve (AUC0-48) 2640 ± 940 ng·h/ml.

Toceranib is highly protein bound at between 91% and 93%. The absolute bioavailability of toceranib when dosed orally at 3.25 mg/kg was determined to be 86%.

Linear pharmacokinetics were seen irrespective of the route of administration at doses up to 5 mg/kg given twice daily. In an in‑vitro study, metabolism of toceranib was primarily to the N-oxide derivative in dogs and cats. There are no in-vivo data on the hepatic metabolism in dogs. No gender differences in pharmacokinetics were observed in-vivo. Following oral administration of toceranib phosphate, approximately 92% of the administered drug is excreted in faeces with another 7% excreted in urine.