Toceranib phosphate: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Toceranib phosphate, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- Palladia® (NADA/ANADA 141-295)
Palladia® NADA 141-295, Original approval, May 22, 2009; sponsor Zoetis Inc.; species: Dogs; foi_id 860; FDA PDF
Indication
Treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumors with or without regional lymph node involvement in dogs
Dose regimen
3.25 mg/kg (1.48 mg/lb) initial; dose reductions of 0.5 mg/kg to a minimum of 2.2 mg/kg, Oral (tablets), with or without food, Every other day, Continuous; dose interruptions up to two weeks to manage adverse reactions; weekly assessments first 6 weeks then every 6 weeks; do not split tablets
Administer an initial dosage of 3.25 mg/kg (1.48 mg/lb) body weight, orally every other day. Dose reductions of 0.5 mg/kg (to a minimum dose of 2.2 mg/kg (1.0 mg/lb) every other day) and dose interruptions (cessation of PALLADIA for up to two weeks) may be utilized, if needed, to manage adverse reactions.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | 68.6 ng/mL (± 12.9 SD) | Single oral dose 3.25 mg/kg, final-formulation tablets, 8 dogs (4M/4F), Study 1560N-60-06-756 | After dosing PHA-291639E orally at 3.25 mg/kg, the mean (± 1SD) Cmax of PHA-291639 was 68.6 (± 12.9) ng/mL. |
| tmax | 7.0 hr | Single oral dose 3.25 mg/kg, 8 dogs | Cmax was observed at 7.0 hr after dosing. |
| half-life | 16.8 hr (harmonic mean; range 13.7 to 19.1 h) | Single oral dose 3.25 mg/kg, 8 dogs | The terminal half-life (harmonic mean), t1/2, was 16.8 hr (range 13.7 to 19.1 h). |
| bioavailability | 76.9% absolute oral (95% CI 57.2% to 103.5%) | Oral 3.25 mg/kg vs IV 1.00 mg/kg, 8 dogs | Absolute oral bioavailability was estimated to be 76.9% with a 95% CI of 57.2% to 103.5%. |
| half-life | 17.5 hr | IV 1.0 mg/kg, 8 dogs | After IV dosing of PHA-291639E at a targeted dose of 1.0 mg/kg, t1/2 was 17.5 hr, approximately the same as after oral dosing, indicating that the elimination is not limited by absorption. |
| clearance | 1.45 L/hr/kg | IV 1.0 mg/kg, 8 dogs | Clearance was moderate at 1.45 L/hr/kg. |
| other | Apparent volume of distribution (Vss) 29.7 L/kg | IV 1.0 mg/kg, 8 dogs | The apparent volume of distribution, Vss, was 29.7 L/kg indicating the drug is well distributed and probably sequestered in various tissues. |
| other | Mean plasma concentration 105 ng/mL (SD ± 9) at 8 hours post-dose | Single oral 3.25 mg/kg in 14 dogs with advanced mast cell tumors (Pryer et al. 2003) | The mean plasma concentration at 8 hours post-dosing was 105 ng/mL (SD, ± 9 ng/mL). |
| other | Food did not significantly influence tablet bioavailability | Fed vs fasted crossover, 12 Beagles, ~3.25 mg/kg (Study 2003-0099) | Food was found to not significantly influence tablet bioavailability. |
Target-animal safety
dose multiples 0X, 0.5X (2.0 mg/kg), 1X (4.0 mg/kg), 1.5X (6.0 mg/kg); duration 13 weeks, once every other day, 1 hour after eating; animals 20 males and 20 females.
The purpose of this study was to demonstrate the safety of PHA- 291639E administered orally once every other day to dogs at 0, 2.0, 4.0, and 6.0 mg/kg (0, 0.5, 1, or 1.5 times the clinical dose), for 13 weeks. Description of Test Animals: Forty Beagle dogs (20 males and 20 females), 24-27 months old, body weight between 6.22 and 15.11 kg before first dosing.
| Finding | Quote |
|---|---|
| Low margin of safety | PHA-291639E has a low margin of safety. |
| Two 6 mg/kg dogs euthanized for treatment-related toxicity (anorexia, melena/hematochezia, weight loss, lameness) | Two dogs (one male and one female) in the 6 mg/kg group were euthanized for treatment-related clinical toxicities. |
| Weight loss, decreased feed consumption, diarrhea; pancreatic, gonadal, adrenal, musculoskeletal and hematopoietic changes including bone marrow suppression | Administration of PHA- 291639E orally once every other day to Beagle dogs at 0, 2.0, 4.0, and 6.0 mg/kg (0, 0.5, 1, or 1.5 times the clinical dose), for 13 consecutive weeks, caused weight loss, decreased feed consumption, diarrhea, and pancreatic, gonadal, adrenal, muscle- locomotor, and hematopoietic changes including bone marrow suppression. |
| Leukopenia in all treated groups; neutropenia dose-dependent | All treated groups (2, 4 and 6 mg/kg) had leukopenia throughout the study compared to placebo. |
| Progressive weight loss at 4 and 6 mg/kg | Dogs in the 4 and 6 mg/kg groups consistently and continually lost weight compared to dogs in the 2 mg/kg group. |
| Dose-related testicular tubular changes / germ cell depletion | In males, the testes showed dose-related tubular changes. |
Effectiveness
Multicenter (10 sites), placebo-controlled, double-blind, randomized (4:3) field study; 6-week masked phase followed by open-label extended phase; 151 dogs enrolled (87 treated, 64 placebo); n = 86 treated, 63 placebo (masked-phase effectiveness analysis); primary endpoint: Objective response rate (complete + partial response, RECIST adapted for canine MCT) at end of 6-week masked phase; result: Objective response 37.2% (32/86) Palladia vs 7.9% (5/63) placebo, P < 0.001; CR 8.1% treated vs 0% placebo
There was a statistically significant improvement in objective response (OR) for PHA-291639E treatment compared to placebo treatment (P < 0.001) as shown in Table 6. The difference in OR rate between groups was not significantly associated with tumor grade (Grade II or III) or tumor burden (presence vs. absence of regional lymph node involvement) (P > 0.05), see Table 7. Table 6: Mast Cell Tumor - primary effectiveness endpoint Effectiveness Parameter Placebo (n = 63) PHA-291639E (n = 86) P-value Objective Response Rate* 7.9% (5/63) 37.2% (32/86) < 0.001
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Diarrhea (any grade) | 46.0% | 26.6% | Placebo (n = 64) PHA-291639E (n = 87) Adverse Reaction Any Grade1 Grade 3 or 4 Any Grade1 Grade 3 or 4 Diarrhea 26.6% 2 3.1% 46.0% 2 6.9% Anorexia 31.3% 6.3% 39.1% 6.9% Lethargy 29.7% 3.1% 35.6% 4.6% Vomiting 32.8% 6.3% 32.2% 9.2% Lameness 9.4% 0.0% 17.2% 0.0% Weight loss 3.1% 2 0.0% 14.9% 2 1.1% |
| Anorexia (any grade) | 39.1% | 31.3% | Placebo (n = 64) PHA-291639E (n = 87) Adverse Reaction Any Grade1 Grade 3 or 4 Any Grade1 Grade 3 or 4 Diarrhea 26.6% 2 3.1% 46.0% 2 6.9% Anorexia 31.3% 6.3% 39.1% 6.9% Lethargy 29.7% 3.1% 35.6% 4.6% Vomiting 32.8% 6.3% 32.2% 9.2% Lameness 9.4% 0.0% 17.2% 0.0% Weight loss 3.1% 2 0.0% 14.9% 2 1.1% |
| Lethargy (any grade) | 35.6% | 29.7% | Placebo (n = 64) PHA-291639E (n = 87) Adverse Reaction Any Grade1 Grade 3 or 4 Any Grade1 Grade 3 or 4 Diarrhea 26.6% 2 3.1% 46.0% 2 6.9% Anorexia 31.3% 6.3% 39.1% 6.9% Lethargy 29.7% 3.1% 35.6% 4.6% Vomiting 32.8% 6.3% 32.2% 9.2% Lameness 9.4% 0.0% 17.2% 0.0% Weight loss 3.1% 2 0.0% 14.9% 2 1.1% |
| Vomiting (any grade) | 32.2% | 32.8% | Placebo (n = 64) PHA-291639E (n = 87) Adverse Reaction Any Grade1 Grade 3 or 4 Any Grade1 Grade 3 or 4 Diarrhea 26.6% 2 3.1% 46.0% 2 6.9% Anorexia 31.3% 6.3% 39.1% 6.9% Lethargy 29.7% 3.1% 35.6% 4.6% Vomiting 32.8% 6.3% 32.2% 9.2% Lameness 9.4% 0.0% 17.2% 0.0% Weight loss 3.1% 2 0.0% 14.9% 2 1.1% |
| Lameness (any grade) | 17.2% | 9.4% | Placebo (n = 64) PHA-291639E (n = 87) Adverse Reaction Any Grade1 Grade 3 or 4 Any Grade1 Grade 3 or 4 Diarrhea 26.6% 2 3.1% 46.0% 2 6.9% Anorexia 31.3% 6.3% 39.1% 6.9% Lethargy 29.7% 3.1% 35.6% 4.6% Vomiting 32.8% 6.3% 32.2% 9.2% Lameness 9.4% 0.0% 17.2% 0.0% Weight loss 3.1% 2 0.0% 14.9% 2 1.1% |
| Weight loss (any grade) | 14.9% | 3.1% | Placebo (n = 64) PHA-291639E (n = 87) Adverse Reaction Any Grade1 Grade 3 or 4 Any Grade1 Grade 3 or 4 Diarrhea 26.6% 2 3.1% 46.0% 2 6.9% Anorexia 31.3% 6.3% 39.1% 6.9% Lethargy 29.7% 3.1% 35.6% 4.6% Vomiting 32.8% 6.3% 32.2% 9.2% Lameness 9.4% 0.0% 17.2% 0.0% Weight loss 3.1% 2 0.0% 14.9% 2 1.1% |
| Neutropenia (any grade, laboratory) | 46.0% | 6.3% | Laboratory Abnormality Any Grade1 Grade 3 or 41 Any Grade1 Grade 3 or 41 Neutropenia 6.3% 2 0.0% 46.0% 2 0.0% |
Extraction notes: TAS margin-of-safety study used 0, 2, 4 and 6 mg/kg every other day, described as 0, 0.5X, 1X and 1.5X 'the clinical dose' (4 mg/kg; the labeled starting dose is 3.25 mg/kg); n_animals expressed as '20 males and 20 females' because the quote spells 'Forty'. Product code PHA-291639E = toceranib phosphate; some quotes carry PDF line-break artifacts ('PHA- 291639E', 'muscle- locomotor') reproduced verbatim. Adverse reactions are from Table 13 (masked phase, placebo n=64 vs treated n=87, any grade).
Reproduce: foi_structured_search(query="Toceranib phosphate") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).