Dirlotapide: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Dirlotapide, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dog.
Products
- Slentrol® (NADA/ANADA 141-260)
Slentrol® NADA 141-260, Original approval, December 12, 2006; sponsor Zoetis Inc.; species: Dog; foi_id 814; FDA PDF
Indication
Management of obesity in dogs.
Dose regimen
0.01 mL/kg once daily for 14 days, then 0.02 mL/kg for the next 14 days, oral, once daily, 5 mg/mL oral solution; after day 28 dose adjusted monthly (increase 100% then 50%) to maintain >= 0.7% weight loss per week; 3-month weight-management phase with 50% then 25% adjustments; maximum 0.2 mL/kg/day
This characterization supports an initial dose of 0.01 mL/kg of dirlotapide oral solution administered once daily by mouth for 14 days followed by 0.02 mL/kg for the next 14 days.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| half-life | 5 to 18 hours (mean elimination half-life range) | oral 2.5-10 mg/kg once daily for 14 days, beagles; increased with dose and repeated dosing | The mean elimination half-life ranged between 5 and 18 hours, and it seemed to increase with dose and with repeated administration. |
| cmax | 63.5 (+ 27.7 SD) ng/mL | Day 1, 0.5 mg/kg oral, obese beagles (3-month margin-of-safety study) | Cmax on Day 1 at the 0.5 mg/kg dose was 63.5 (+ 27.7 SD) ng/mL and AUC0-last was 304 (+ 134) ng*h/mL. |
| auc | 304 (+ 134) ng*h/mL (AUC0-last) | Day 1, 0.5 mg/kg oral, obese beagles | Cmax on Day 1 at the 0.5 mg/kg dose was 63.5 (+ 27.7 SD) ng/mL and AUC0-last was 304 (+ 134) ng*h/mL. |
| clearance | primarily biliary secretion | dirlotapide and one metabolite detected in bile in a greater-than-dose-proportional manner | Dirlotapide clearance appears to be primarily via biliary secretion. |
| other | systemic exposure highest on Day 29, then decreased during the subsequent two months | 0.5-2.5 mg/kg/day oral, 3 months | Systemic exposure was highest on Day 29, and decreased during the subsequent two months of treatment. |
Target-animal safety
dose multiples 1X (0.5 mg/kg, reduced to 0.36-0.4 mg/kg), 3X (1.5 mg/kg), 5X (2.5 mg/kg); duration 90 consecutive days once daily, plus 1-month post-treatment period for selected dogs; animals 38.
The 38 animals were allocated into 4 groups of dogs. Selected dogs from the 1.5 mg/kg treatment group and 0.3 mL/kg control group were maintained for a 1-month post-treatment period following 3 months of dirlotapide treatment.
| Finding | Quote |
|---|---|
| Dose-related vomiting in the first 14 days: 5/6 (2.5 mg/kg), 9/12 (1.5 mg/kg), 2/6 (0.5 mg/kg) | During the first 14 days of treatment, 5 of 6 dogs (87%) in the 2.5 mg/kg group, 9 of 12 (75%) in the 1.5 mg/kg group, and 2 of 6 (33%) in the 0.5 mg/kg treatment group vomited. |
| Body weight fell 17-39% from baseline in treated dogs | Body weight decreased between 17% and 39% from baseline for dirlotapide-treated dogs. |
| Mild to moderate ALT/AST increases at 1.5 and 2.5 mg/kg; two high-dose dogs had AST >100 U/L with ALT >500 U/L | In the high dose (2.5 mg/kg) group, two of six dogs (one male and one female) had AST elevations >100 U/L combined with ALT elevations >500 U/L and a mild increase in bile acids. |
| Dose-related decreases in serum cholesterol and HDL | Dogs treated wi th dirlotapide revealed a dose-related decrease in serum cholesterol (P=0.0001) and high-density lipoprotein (HDL) concentration (P=0.0001) by day 28 that remained relatively constant for the remainder of the 3-month treatment period. |
| Reduced plasma vitamins A and E without clinical deficiency | Decreases in vitamin A and E plasma concentrations were observed early in treatment for all dirlotapide-treated groups. No clinical or histopathological signs of vitamin deficiency were observed. |
| Lipid vacuoles in small-intestinal enterocytes; hepatic glycogen accumulation; reversible after 1-month recovery | On histopathological examination, the enterocytes of the small intestine contained lipid vacuoles in the villus tips. Dilated lacteals were observed in some dogs. Hepatic glycogen accumulation was observed in all treatment groups. There were no significant treatment-related findings at the end of the 1-month recovery period. |
| Well tolerated at 0.4 mg/kg for 3 months; higher doses increased vomiting and salivation | Dirlotapide was well-tolerated when administered once daily for three months at 0.4 mg/kg to healthy beagle dogs. |
Effectiveness
Randomized, masked, corn-oil-controlled field dose-confirmation study (1962C-60-03-671) at 23 clinics in the US and Canada; 1 control : 2 dirlotapide allocation; escalating 0.0045 then 0.009 mL/lb once daily for 28 days then monthly adjustment for 4 months; n = 258 (119 males, 139 females); primary endpoint: Total percent body weight loss at day 112 and percent of dogs achieving 13% body weight loss at day 112; result: Least squares mean weight change -11.8% dirlotapide vs -3.9% control (P<0.0001); 39% of treated dogs vs 5.3% of controls lost >13% body weight (P=0.0002); 58% of owners reported increased activity; final mean dose 0.12 mg/lb (0.05-0.24)
The study included 258 client owned obese dogs (119 males and 139 fem ales) of various breeds and age (range of 1 to 14 years) presented to 23 veterinary clinics in the US and Canada for weight loss.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Vomiting | 24.7% | 21.6% | Vomiting 21.6% 24.7% |
| Diarrhea | 12.4% | 6.8% | Diarrhea 6.8% 12.4% |
| Lethargy | 9.4% | 3.4% | Lethargy 3.4% 9.4% |
| Anorexia | 7.6% | 2.3% | Anorexia 2.3% 7.6% |
| Constipation | 2.4% | 1.1% | Constipation 1.1% 2.4% |
| Dehydration | 1.2% | 0% | Dehydration 0% 1.2% |
Extraction notes: 2006 original approval. Adverse reaction rows are from field-study Table 3 (Control n = 88, Dirlotapide n = 170); columns in order Control %, Dirlotapide %. Effectiveness analyses used n = 74/132 (percent weight change) and 75/141 (13% loss endpoint) after withdrawals. PK values come from the target-animal-safety studies (no dedicated PK section). The pivotal margin-of-safety study is the 3-month 0/0.5/1.5/2.5 mg/kg study in obese beagles (Table 9 lists 10 + 4 controls, 6, 12 and 6 dogs). A 14-day 2.5-10 mg/kg tolerance study, a 1-year use-dose study in 72 Labradors (retinal/cataract findings judged breed-related) and a 9-month SEDDS-formulation study are also summarized. Treated dogs in the field study had more ALT (9.9% vs 4.8%) and AST (9.2% vs 6.0%) elevations than controls; one treated Beagle developed seizures and one treated Dachshund a hepatopathy. Some words in the extracted text are split (e.g. 'fem ales', 'wi th'); quotes reproduce the extraction.
Reproduce: foi_structured_search(query="Dirlotapide") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).