Tigilanol tiglate: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Tigilanol tiglate, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- STELFONTA® (NADA/ANADA 141-541)
STELFONTA® NADA 141-541, Original approval, November 16, 2020; sponsor QBiotics Group Ltd.; species: Dogs; foi_id 9988; FDA PDF
Indication
Treatment of non-metastatic cutaneous mast cell tumors and non-metastatic subcutaneous mast cell tumors located at or distal to the elbow or the hock in dogs
Dose regimen
0.5 mg per cm3 of tumor volume (1.0 mg/mL solution, i.e. 0.5 mL/cm3); maximum 0.25 mg/kg, maximum total 5.0 mg, minimum total 0.1 mg, Intratumoral injection (fanned throughout the tumor from a single entry point), Single treatment; optional second treatment on Day 30 if incomplete response, Tumor volume must not exceed 10 cm3; concomitant prednisone/prednisolone, famotidine and diphenhydramine required to limit mast cell degranulation
STELFONTA® was provided at a concentration of 1.0 mg/mL and dosed at 0.5 mg/cm3 of tumor volume. The maximum dose was no greater than 0.25 mg/kg, the maximum total dose was 5.0 mg, and the minimum total dose was 0.1 mg.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | 11.33±4.52 ng/mL (mean ± SD, Day 22) | 0.025 mg/kg IV infusion (15 min) once weekly x 4, healthy Beagles, margin-of-safety study 1014-1082 | pharmacokinetic parameters on Day 22 for STELFONTA® Parameter 0.025 mg/kg Group 0.05 mg/kg Group 0.075 mg/kg Group Cmax (ng/mL) 11.33±4.52 34.64±10.24 56.78±26.76 AUClast (hr*ng/mL) 4.92±1.20 10.18±2.92 16.96±5.96 |
| cmax | 34.64±10.24 ng/mL (mean ± SD, Day 22) | 0.05 mg/kg IV infusion once weekly x 4, healthy Beagles | pharmacokinetic parameters on Day 22 for STELFONTA® Parameter 0.025 mg/kg Group 0.05 mg/kg Group 0.075 mg/kg Group Cmax (ng/mL) 11.33±4.52 34.64±10.24 56.78±26.76 AUClast (hr*ng/mL) 4.92±1.20 10.18±2.92 16.96±5.96 |
| cmax | 56.78±26.76 ng/mL (mean ± SD, Day 22) | 0.075 mg/kg IV infusion once weekly x 4, healthy Beagles | pharmacokinetic parameters on Day 22 for STELFONTA® Parameter 0.025 mg/kg Group 0.05 mg/kg Group 0.075 mg/kg Group Cmax (ng/mL) 11.33±4.52 34.64±10.24 56.78±26.76 AUClast (hr*ng/mL) 4.92±1.20 10.18±2.92 16.96±5.96 |
| auc | 4.92±1.20 hr*ng/mL (AUClast, mean ± SD, Day 22) | 0.025 mg/kg IV, healthy Beagles | pharmacokinetic parameters on Day 22 for STELFONTA® Parameter 0.025 mg/kg Group 0.05 mg/kg Group 0.075 mg/kg Group Cmax (ng/mL) 11.33±4.52 34.64±10.24 56.78±26.76 AUClast (hr*ng/mL) 4.92±1.20 10.18±2.92 16.96±5.96 |
| auc | 10.18±2.92 hr*ng/mL (AUClast, mean ± SD, Day 22) | 0.05 mg/kg IV, healthy Beagles | pharmacokinetic parameters on Day 22 for STELFONTA® Parameter 0.025 mg/kg Group 0.05 mg/kg Group 0.075 mg/kg Group Cmax (ng/mL) 11.33±4.52 34.64±10.24 56.78±26.76 AUClast (hr*ng/mL) 4.92±1.20 10.18±2.92 16.96±5.96 |
| auc | 16.96±5.96 hr*ng/mL (AUClast, mean ± SD, Day 22) | 0.075 mg/kg IV, healthy Beagles | pharmacokinetic parameters on Day 22 for STELFONTA® Parameter 0.025 mg/kg Group 0.05 mg/kg Group 0.075 mg/kg Group Cmax (ng/mL) 11.33±4.52 34.64±10.24 56.78±26.76 AUClast (hr*ng/mL) 4.92±1.20 10.18±2.92 16.96±5.96 |
| half-life | approximately half an hour (range 0.29 - 1.17 hours) | IV infusion, Days 1 and 22, healthy Beagles | The terminal elimination half-life (T1/2) was approximately half an hour (range 0.29 - 1.17 hours) on both Days 1 and 22. |
| tmax | 0 - 1 minute post end of infusion (one profile at 5 minutes) | IV infusion, healthy Beagles | The time range for reaching maximum plasma concentration (Tmax) was 0 - 1 minute post-EOI in all except one profile, for which Tmax occurred at the subsequent time point, at 5 minutes post-EOI. |
| cmax | 0.356 ng/mL to 13.8 ng/mL (range) | Intratumoral injection 0.5 mL/cm3 (0.002-0.145 mg/kg), 10 client-owned dogs with MCT, pilot study QB46-C02 | Pharmacokinetics: The following range of pharmacokinetic parameters were determined in this study: maximum plasma concentration (Cmax) ranged from 0.356 ng/mL to 13.8 ng/mL, area under the plasma concentration time-curve to the last quantifiable plasma concentration (AUClast) ranged from 2.25 h*ng/mL to 31.24 h*ng/mL, and elimination half-life (T1/2) ranged from 2.85 to 36.87 hours. |
| auc | 2.25 h*ng/mL to 31.24 h*ng/mL (AUClast range) | Intratumoral injection, 10 client-owned dogs with MCT | Pharmacokinetics: The following range of pharmacokinetic parameters were determined in this study: maximum plasma concentration (Cmax) ranged from 0.356 ng/mL to 13.8 ng/mL, area under the plasma concentration time-curve to the last quantifiable plasma concentration (AUClast) ranged from 2.25 h*ng/mL to 31.24 h*ng/mL, and elimination half-life (T1/2) ranged from 2.85 to 36.87 hours. |
| half-life | 2.85 to 36.87 hours (range) | Intratumoral injection, 10 client-owned dogs with MCT | Pharmacokinetics: The following range of pharmacokinetic parameters were determined in this study: maximum plasma concentration (Cmax) ranged from 0.356 ng/mL to 13.8 ng/mL, area under the plasma concentration time-curve to the last quantifiable plasma concentration (AUClast) ranged from 2.25 h*ng/mL to 31.24 h*ng/mL, and elimination half-life (T1/2) ranged from 2.85 to 36.87 hours. |
Target-animal safety
dose multiples 0 (vehicle), 0.025 mg/kg IV (0.1X the 0.25 mg/kg maximum label dose), 0.05 mg/kg IV (0.2X), 0.075 mg/kg IV (0.3X); duration 15-minute IV infusion once weekly for 4 doses (Days 1, 8, 15, 22) plus 14-day recovery in 2M/2F per group; animals 24 males, 24 females.
The objective of this study was to determine the toxicity and toxicokinetic profile of STELFONTA® following intravenous (IV) infusion to Beagle dogs once weekly on four occasions (total of four injections), and to assess the reversibility of any changes following a 14-day recovery period. The study was conducted in accordance with Organization of Economic Co-operation and Development (OECD) Good Laboratory Practice GLP. Study Animals: Forty-eight (24 males, 24 females), intact, 6 to 8-month-old Beagle dogs, ranging in weight from 5.1-7.5 kg at study initiation were randomly assigned to four study groups consisting of 6 males and 6 females each.
| Finding | Quote |
|---|---|
| All dogs survived | All dogs survived the study until the scheduled termination dates. |
| Vomiting during/after dosing in 21/36 treated dogs, none in vehicle controls | Vomiting only occurred in the STELFONTA® treatment groups, and not in the vehicle control group, during or immediately after dosing on all dosing days, affecting 21/36 of the dogs. |
| Dose-dependent limited use of infused limb (8/12 at 0.075 mg/kg) | Limited use of the limb that received the infusion was seen 13/48 dogs in all groups, including vehicle control, but was dose-dependent, occurring in 8/12 dogs in the 0.075 mg/kg group. |
| Infusion-site wound formation (one 0.025 mg/kg dog; severe wound in one 0.075 mg/kg dog) | Wound development at the infusion site was observed in one dog in the 0.025mg/kg group that started a few days after the first dose and a severe wound was observed in one dog in the 0.075 mg/kg group |
| ALT elevations in two 0.075 mg/kg dogs | Two dogs in the 0.075 mg/kg group had elevations in ALT on Day 23. |
| Summary of test-article-related findings | Test article-related findings included vomiting/retching, wound formation, decreased activity, loose feces, salivation, tremors, limited use of the leg that received the infusion, weakness, increased water consumption, and erythema and edema at the infusion site. |
| Reversible, dose-dependent increase in heart rate (cardiovascular telemetry study) | This study demonstrated that STELFONTA® causes a reversible increase in heart rate. |
Effectiveness
Multicenter (11 US sites), prospective, randomized (2:1), investigator- and owner-masked, sham-controlled (untreated control) field study; 123 dogs enrolled (81 Stelfonta, 42 control); all dogs received prednisone/prednisolone, famotidine and diphenhydramine; n = 118 (80 STELFONTA, 38 untreated control); primary endpoint: Complete response (CR) of the target tumor at Day 28 (RECIST v1.1, two masked evaluators); result: CR at Day 28: 75% (60/80) STELFONTA vs 5.3% (2/38) control, p<0.0001; objective response (CR+PR) 80.0% vs 5.3%; 96.5% of Day-28 CR dogs disease-free at Day 84
Results: Effectiveness was evaluated in 118 dogs (80 dogs in the STELFONTA® group and 38 dogs in the untreated control group). At Day 28, a statistically significant difference (p<0.0001) was seen between the STELFONTA® and untreated control groups, with 75% of STELFONTA® treated dogs and 5.3% of untreated control dogs recorded as CR.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Wound formation | 94.0% (110/117) | 7.1% (3/42) | STELFONTA® 1st Treatment (n = 117) STELFONTA® 2nd Treatment (n = 18) Untreated Control (n = 42) Wound formation 110 (94.0%) 12 (66.7%) 3 (7.1%) Injection site pain 61 (52.1%) 7 (38.9%) 1 (2.4%) Lameness in treated limb 29 (24.8%) 2 (11.1%) 1 (2.4%) Vomiting 24 (20.5%) 3 (16.7%) 4 (9.5%) Diarrhea 24 (20.5%) 3 (16.7%) 2 (4.8%) Hypoalbuminemiaa 21 (18.0%) 2 (11.1%) 1 (2.4%) |
| Injection site pain | 52.1% (61/117) | 2.4% (1/42) | STELFONTA® 1st Treatment (n = 117) STELFONTA® 2nd Treatment (n = 18) Untreated Control (n = 42) Wound formation 110 (94.0%) 12 (66.7%) 3 (7.1%) Injection site pain 61 (52.1%) 7 (38.9%) 1 (2.4%) Lameness in treated limb 29 (24.8%) 2 (11.1%) 1 (2.4%) Vomiting 24 (20.5%) 3 (16.7%) 4 (9.5%) Diarrhea 24 (20.5%) 3 (16.7%) 2 (4.8%) Hypoalbuminemiaa 21 (18.0%) 2 (11.1%) 1 (2.4%) |
| Lameness in treated limb | 24.8% (29/117) | 2.4% (1/42) | STELFONTA® 1st Treatment (n = 117) STELFONTA® 2nd Treatment (n = 18) Untreated Control (n = 42) Wound formation 110 (94.0%) 12 (66.7%) 3 (7.1%) Injection site pain 61 (52.1%) 7 (38.9%) 1 (2.4%) Lameness in treated limb 29 (24.8%) 2 (11.1%) 1 (2.4%) Vomiting 24 (20.5%) 3 (16.7%) 4 (9.5%) Diarrhea 24 (20.5%) 3 (16.7%) 2 (4.8%) Hypoalbuminemiaa 21 (18.0%) 2 (11.1%) 1 (2.4%) |
| Vomiting | 20.5% (24/117) | 9.5% (4/42) | STELFONTA® 1st Treatment (n = 117) STELFONTA® 2nd Treatment (n = 18) Untreated Control (n = 42) Wound formation 110 (94.0%) 12 (66.7%) 3 (7.1%) Injection site pain 61 (52.1%) 7 (38.9%) 1 (2.4%) Lameness in treated limb 29 (24.8%) 2 (11.1%) 1 (2.4%) Vomiting 24 (20.5%) 3 (16.7%) 4 (9.5%) Diarrhea 24 (20.5%) 3 (16.7%) 2 (4.8%) Hypoalbuminemiaa 21 (18.0%) 2 (11.1%) 1 (2.4%) |
| Diarrhea | 20.5% (24/117) | 4.8% (2/42) | STELFONTA® 1st Treatment (n = 117) STELFONTA® 2nd Treatment (n = 18) Untreated Control (n = 42) Wound formation 110 (94.0%) 12 (66.7%) 3 (7.1%) Injection site pain 61 (52.1%) 7 (38.9%) 1 (2.4%) Lameness in treated limb 29 (24.8%) 2 (11.1%) 1 (2.4%) Vomiting 24 (20.5%) 3 (16.7%) 4 (9.5%) Diarrhea 24 (20.5%) 3 (16.7%) 2 (4.8%) Hypoalbuminemiaa 21 (18.0%) 2 (11.1%) 1 (2.4%) |
| Hypoalbuminemia | 18.0% (21/117) | 2.4% (1/42) | STELFONTA® 1st Treatment (n = 117) STELFONTA® 2nd Treatment (n = 18) Untreated Control (n = 42) Wound formation 110 (94.0%) 12 (66.7%) 3 (7.1%) Injection site pain 61 (52.1%) 7 (38.9%) 1 (2.4%) Lameness in treated limb 29 (24.8%) 2 (11.1%) 1 (2.4%) Vomiting 24 (20.5%) 3 (16.7%) 4 (9.5%) Diarrhea 24 (20.5%) 3 (16.7%) 2 (4.8%) Hypoalbuminemiaa 21 (18.0%) 2 (11.1%) 1 (2.4%) |
Extraction notes: The margin-of-safety study used the IV route (0.025/0.05/0.075 mg/kg once weekly x4) because SC injection has a low maximum tolerable dose; these are fractions of the 0.25 mg/kg maximum labeled intratumoral dose but IV gave higher systemic exposure than intratumoral dosing. n_animals given as '24 males, 24 females' because the quote spells 'Forty-eight'. The safety overview paragraph misstates the high IV dose as 0.75 mg/kg; the study design section (0.075 mg/kg) was used. Adverse reactions from Table II.4: 1st STELFONTA treatment (n=117, includes 36 control dogs treated on Day 30) vs untreated control (n=42). Two deaths from suspected mast cell degranulation occurred in pilot studies in dogs that did not receive the required concomitant medications.
Reproduce: foi_structured_search(query="Tigilanol tiglate") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).