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Toceranib phosphate is a small molecule that has both direct antitumor and antiangiogenic activity. In non-clinical pharmacology studies, toceranib selectively inhibited the tyrosine kinase activity of several members of the split kinase receptor tyrosine kinase (RTK) family, some of which are implicated in tumor 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 (Kit) in both biochemical and cellular assays. Toceranib has been shown to exert an antiproliferative effect on endothelial cells in vitro. Toceranib treatment can induce cell cycle arrest and subsequent apoptosis in tumor cell lines expressing activating mutations in the split kinase RTK, ckit. Canine mast cell tumor growth is frequently driven by activating mutations in c-kit.1, 2
Other compounds in the antiangiogenesis class of antineoplastic agents are known to increase embryolethality and fetal abnormalities. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of PALLADIA should be expected to result in adverse effects on the pregnancy in the bitch.
Following intravenous administration, the pharmacokinetics of toceranib is characterized by a very large volume of distribution (>20 L/kg, indicating partitioning into tissues), a terminal elimination half-life of about 16 hrs, and a clearance of >1 L/hr/kg. With a regimen of 3.25 mg free base equivalent (fbe)/kg doses of toceranib administered by tablet orally every other day for 2 weeks (7 doses), the pharmacokinetic parameters of toceranib in plasma in healthy Beagle dogs (between 7.2 – 12.5 kg) are shown in the table below.
|Pharmacokinetic Parameters(Mean + 1SD)||Total (n=11;6M, 5F)Dose 1||Total (n=10; 5M, 5F)Dose 7|
|Elimination half-life, t1/2 (h)||16.4 ± 3.6||17.2 ± 3.9|
|Time to maximum plasma concentration, Tmax (h)||5.3 ± 1.6||6.2 ± 2.6|
|Maximum plasma concentration, Cmax (ng/mL)||86 ± 22||109 ± 41|
|Cmin (ng/mL)*, †||12.7 ± 6.0||18.7 ± 8.3|
|Area under the plasma concentration time-curve, AUC0-48 (ng∙h/mL)*||1833 ± 508||2635 ± 939|
Oral bioavailability of toceranib is 77%. PALLADIA is highly protein bound at 91% to 93%.
It should be noted that despite the homogeneity of subjects included in this study, large between-subject variability was observed. Regardless of the route of administration, linear pharmacokinetics has been observed at doses up to 5 mg/kg twice daily. Using an in vitro hepatocyte and liver microsome test system, the Z isomer was found to be metabolized to the N-oxide derivative of toceranib in dogs, humans, cats, and rats. Although a small gender difference was observed in the in vitro study (81% conversion in male dogs, 56% conversion in female dogs) no differences in toceranib pharmacokinetics was observed in vivo. The effects of renal impairment, hepatic impairment or breed on the pharmacokinetics of toceranib have not been investigated.
The effectiveness and safety of PALLADIA oral tablets for the treatment of mast cell tumors was evaluated in a randomized, placebo-controlled, double-masked, multicenter clinical field study. The purpose of this study was to evaluate the effectiveness and safety of PALLADIA in the treatment of mast cell tumors in dogs that had recurrent measurable disease after surgery and to evaluate objective response (complete or partial response). PALLADIA treatment was compared to placebo treatment using response rates at the end of the 6-week masked phase. Response rates were determined using the National Cancer Institute’s Response Evaluation Criteria in Solid Tumors Guideline3 which was modified specifically for the evaluation of canine mast cell tumors.
One-hundred-fifty-three dogs were randomly assigned to treatment with either 3.25 mg/kg PALLADIA (n = 88) or placebo (n = 65) orally, every other day for 6 weeks, or until disease progression or withdrawal from the study for another cause. Treatment was unmasked at the time of disease progression: dogs receiving placebo were then offered crossover to open-label PALLADIA; dogs receiving PALLADIA were discontinued from the study. Dogs were required to have Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement. At least 1 tumor had to be at least 20 mm in diameter. Dogs had a limit of 1 completed radiation protocol and a limit of 1 prior systemic chemotherapy regimen. Dogs with evidence of systemic mast cell tumor were excluded. Treatment with systemic corticosteroids during the study or within 14 days prior to study initiation was not permitted. If needed to manage adverse reactions, dose interruptions (cessation of PALLADIA for up to 2 weeks) were prescribed and/or dosage was reduced to as low as 2.2 mg/kg.
The effectiveness analysis showed a statistically significant advantage for PALLADIA over placebo in the primary effectiveness endpoint of objective response at the end of the six week masked phase. Objective response is complete response + partial response. Partial response is ≥ 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum, non-progression of nontarget lesions and appearance of no new lesions.
|Effectiveness Parameter||Placebo (n = 63)||PALLADIA (n = 86)||P-value|
|Objective Response Rate *||7.9%||37.2%||< 0.001|
During the study, PALLADIA was administered concomitantly with other medications such as antimicrobials, H-2 receptor blockers, antihistamines, anti-emetics, non-steroidal antiinflammatory drugs, locally-acting anti-ulcer medications, opiate gastrointestinal motility modifiers, opioids, vaccines, anthelmintics, antiparasitics, and topical/ophthalmic/otic corticosteroid preparations. During the open-label phase only, 5 dogs received a brief course of short-acting corticosteroids.
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