Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant, a novel therapeutic for the pain and inflammation of osteoarthritis in dogs

Abstract

A new anti-inflammatory drug for pain (grapiprant) was recently shown to have minimal side effects following chronic (9-month) daily oral dose of 6 or 50 mg/kg suspension. The current study compares the pharmacokinetics of the formulation used in the chronic safety study to those of the tablet formulation that will be marketed upon FDA approval. Sixteen Beagle dogs were randomized to receive single doses of either 6 or 50 mg/kg grapiprant as both suspension and table formulations within a cross-over design with a 15-day washout. Clinical observations were vomiting in one high-dose suspension dog and loose stools in two dogs, one in each 6 mg/kg formulation group. For both formulations, grapiprant reached a maximum concentration within two hours. The tablet formulation had better bioavailability, with AUC values 34% higher at 6 mg/kg and 64% higher at 50 mg/kg compared to the suspension. Results on Day 0 were similar to those reported on Day 15, suggesting little to no accumulation. Using conversion factors of 1.34 and 1.64, these findings suggest that the 6 and 50 mg/kg suspension doses are equivalent to 4.5 and 30 mg/kg tableted doses, respectively. Combining these findings with the 9-month safety study demonstrates that safety was evaluated at doses approximately 15-fold above the demonstrated therapeutic dose of 2 mg/kg and 10-fold over the 'safety dose', defined as the maximum dose a dog of any body weight could receive when dosed at 2 mg/kg with whole or half-tablets.

Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs

“…In a recently published study (Rausch‐Derra et al ., ), grapiprant PK parameters between tablet and suspension administration at the doses of 6 and 50 mg/kg were shown to have significant variabilities. Specifically, AUC values for the 50 mg/kg group exhibited 20‐ and 25‐fold exposure for suspension and tablet, respectively, compared with those exhibited by the 6 mg/kg group.…”

Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation

“…Safety studies in laboratory dogs have demonstrated an excellent safety profile, and a wide safety margin, and this has been confirmed in two large field effectiveness studies in dogs with OA (Rausch‐Derra et al . ,b). The relative lack of toxic effects with grapiprant compared to those that have been reported in dogs treated with COX‐inhibiting NSAIDs is consistent with grapiprant's unique mechanism of action, although until FDA review and approval, claims of safety and effectiveness cannot be made.…”

“…As part of development of grapiprant for FDA approval for dogs with OA, a safety study in healthy Beagles investigated the effects of daily orally administered doses up to 50 mg kg −1 day −1 oral suspension (equivalent to approximately 30.5 mg kg −1 day −1 of the tablet formulation) for nine consecutive months (Rausch‐Derra et al . ,b). There were no drug‐related effects on liver enzyme values, BUN/creatinine, or platelet function.…”

Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan‐induced inflammatory pain model in the rabbit

“…In a previous clinical study, 2 mg/kg grapiprant (administered per OS once a day for 4 weeks) produced effective antinociception in dogs with natural osteoarthritis (Rausch‐Derra et al ., ,b). In the present study, grapiprant produced thermal antinociception from 1 h up to 10 h. This is in line with former studies using rat models to demonstrate garpiprant's ability to reduce acute and chronic pain and inflammation (Nakao et al ., ; RaQualia, ,b).…”

“…As prostanoids are important in a variety of physiological functions, the adverse effects associated with the inhibition of the cycloxygenase enzymes such as renal, gastrointestinal and hepatic toxicity and coagulopathies are minimized. This drug has been shown to have a very safe and effective profile in dogs (Rausch‐Derra et al ., ,b) and cats (Rausch‐Derra & Rhodes, ). However, lagomorphs may react to grapiprant differently to cats and dogs; hence, a PK/PD study in rabbits is essential to understand the effectiveness of this drug.…”