Galliprant: Product Information (Page 2 of 6)
Information for Dog Owners:
Owners should be advised of the potential for adverse reactions and be informed of the clinical signs associated with drug intolerance. Adverse reactions may include vomiting, diarrhea, decreased appetite, and decreasing albumin and total protein.
Appetite and stools should be monitored and owners should be advised to consult with their veterinarian if appetite decreases or stools become abnormal.
Clinical Pharmacology:
Grapiprant is a prostaglandin E2 (PGE2 ) EP4 receptor antagonist; a non- cyclooxygenase inhibiting, non-steroidal, anti-inflammatory drug. Grapiprant has a canine EP4 receptor binding affnity (Ki) of 24 nM.
Prostaglandins have a wide variety of physiologic effects. Prostaglandin E2 (PGE2 ) is a prostanoid that exerts its effects via four receptors, EP1, EP2, EP3, and EP4. PGE2 is involved in mediating inflammatory pain, vasodilation, increasing vascular permeability; as well as gastrointestinal homeostasis, renal function and reproductive functions. The EP4 receptor is important in mediating pain and inflammation as it is the primary mediator of the PGE2 -elicited sensitization of sensory neurons1 and PGE2 -elicited inflammation.2 Grapiprant blocks PGE2 -elicited pain and inflammation by antagonizing the EP4 receptor.
The EP4 receptor, along with the EP1, EP2 and EP3 receptors, is involved in PGE2 mediated effects on gastrointestinal homeostasis and renal function. PGE2 effects mediated solely by the EP4 receptor are stimulation of mucus secretion in the stomach and large intestine, stimulation of acid secretion in the stomach, inhibition of small intestine motility and inhibition of cytokine expression in the large intestine.3 While PGE2 gastroprotective action is mediated by EP1, the healing- promoting action of PGE2 in the stomach is mediated by the EP4 receptor.4 In the kidney, the PGE2 antinatiuretic effect is mediated by the EP4 receptor.5
EP4 receptors are abundantly expressed in the heart of dogs,6 the clinical relevance of which is unknown. The EP4 receptor is not involved in generation of pyrexia.
Grapiprant is not a potential inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 mediated metabolism pathways. Grapiprant is a substrate of P-glycoprotein transport. In vitro metabolism with dog liver microsomes identified two oxidative metabolites, M3 (hydroxyl) and M5 (N-dealkylation).
The pharmacokinetic characterization of grapiprant following oral administration of GALLIPRANT tablets to healthy Beagles is provided in the table below.
| 1 Study 1 was a food effect determination study. | ||||
| 2 Study 2 was a PK bridging study conducted using 60 mg GALLIPRANT tablets at 6 mg/kg dose and 5 X 100 mg GALLIPRANT tablets at 50 mg/kg dose. | ||||
| 3 Median (Range) | ||||
| Study | Study 11 | Study 11 | Study 22 | Study 22 |
| PK Parameter | 2 mg/kg(n = 10)(Fasted) | 2 mg/kg(n = 10)(Fed) | 6 mg/kg(n = 8)(Fasted) | 50 mg/kg(n = 8)(Fasted) |
| Tmax3 (hr) | 1.0(0.5 – 1.03) | 1.0(0.5 – 8.07) | 1.0(1.0 – 2.0) | 2.0(1.0 – 4.0) |
| Cmax (ng/mL) | 1210(341) | 278(179) | 5720(3220) | 98500(13100) |
| AUC(0-inf) (ng*hr/mL) | 2790(982) | 1200(523) | 17800(5520) | 414000(73700) |
| T1/2(hr) | 4.60(4.19) | 5.67(3.27) | 5.01(1.95) | 5.21(1.66) |
| Fed/Fasted Relative Bioavailability Geometric Mean Ratio of AUC(90% Confidence Limits) | 0.37 (0.28 – 0.46) | NA | ||
Grapiprant is absorbed rapidly following an oral dose of the GALLIPRANT; with Cmax values achieved within approximately 2 hr post-dose (Tmax). Intake of the tablet with food significantly reduces the oral bioavailability, with mean Cmax and AUC grapiprant values reduced 4-fold and 2-fold, respectively. The systemic grapiprant exposure increases in a greater than dose proportional manner.
The mean terminal elimination half-life (T1/2) ranges between 4.60 to 5.67 hr. Following once daily dosing, negligible drug accumulation in the blood is anticipated. Following an oral dose of radiolabeled grapiprant to dogs, the majority of the dose was excreted within the first 72 hr (84%) and approximately 88.7% of the dose was excreted in 192 hr. In a bile duct cannulated dog study, approximately 55.6%, 15.1% and 19.1% of the dose was excreted in bile, urine and feces, respectively, suggesting the high oral bioavailability of grapiprant in dogs (> 70%). Four metabolites were identified; two hydroxylated metabolites, one N-deamination metabolite (major metabolite urine (3.4%) and feces (7.2%)) and one N-oxidation metabolite. Metabolite activity is not known. Plasma protein binding of grapiprant was ~95%.
Effectiveness:
Two hundred and eighty five (285) client-owned dogs were enrolled in the study and evaluated for field safety. GALLIPRANT-treated dogs ranging in age from 2 to 16.75 years and weighing between 4.1 and 59.6 kgs (9 – 131 lbs) with radiographic and clinical signs of osteoarthritis were enrolled in a placebo-controlled, masked field study. Dogs had a 7-day washout from NSAID or other current OA therapy. Two hundred and sixty two (262) of the 285 dogs were included in the effectiveness evaluation. Dogs were assessed for improvements in pain and function by the owners using the Canine Brief Pain Inventory (CBPI) scoring system.7 A statistically significant difference in the proportion of treatment successes in the GALLIPRANT group (63/131 or 48.1%) was observed compared to the vehicle control group (41/131 or 31.3%). GALLIPRANT demonstrated statistically significant differences in owner assessed pain and function. The results of the field study demonstrate that GALLIPRANT, administered at 2 mg/kg (0.9 mg/pound) once daily for 28 days, was effective for the control of pain and inflammation associated with osteoarthritis.
Animal Safety:
In a 9-month toxicity study, grapiprant in a methylcellulose suspension was administered by oral gavage once daily to healthy Beagles at doses of 1, 6, and 50 mg/kg/day. Based on a relative bioavailability study comparing grapiprant in methylcellulose suspension to GALLIPRANT tablets, the corresponding equivalent doses were 0.75 mg/kg (0.12X – 0.25X), 4.44 mg/kg (0.72X – 1.48X) and 30.47 mg/kg (4.88X – 10.16X) of the GALLIPRANT tablets. Four animals/sex were used in each dose group and 2 additional animals/sex were used in the 50 mg/kg dose group to evaluate recovery after drug cessation. Vomiting and soft-formed or mucus stool were observed in all groups, including controls, with higher incidence in grapiprant-treated dogs. Decreases in serum albumin and total protein were seen with increasing doses of grapiprant. Hypoalbuminemia and hypoproteinemia were reversible when treatment was discontinued. Three treated dogs and one control dog had elevated alkaline phosphatase values. One animal in the 50 mg/kg group (equivalent to 30.47 mg/kg of tablet formulation) had mild regeneration of the mucosal epithelium of the ileum.
In a field study conducted in 366 client-owned dogs to evaluate GALLIPRANT at doses of 2 mg/kg once daily, 5 mg/kg once daily, 4 mg/kg twice daily, or placebo twice daily, the most common adverse reactions related to treatment were diarrhea, vomiting and inappetence. Changes in clinical pathology included concurrent elevations of alkaline phosphatase and alanine aminotransferase values on Day 28, and dose-dependent decreases in total protein values. There was no clinical impact related to these clinical pathology changes.
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