title: 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 AUClastvalues 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.
authors.affiliation: Aratana Therapeutics, Inc., Leawood, KS, USA. lrausch-derra@aratana.com.
authors.forename: L C
authors.initials: LC
authors.lastname: Rausch-Derra
authors.affiliation: Aratana Therapeutics, Inc., Leawood, KS, USA.
authors.forename: L
authors.initials: L
authors.lastname: Rhodes
authors.affiliation: BioSTAT Consultants, Inc., Portage, MI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Freshwater
authors.affiliation: Ricerca Biosciences, LLC, Concord, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Hawks
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000662:veterinary*; D008297:Male; D010003:Osteoarthritis / Q000188:drug therapy / Q000662:veterinary*; D010146:Pain / Q000209:etiology / Q000662:veterinary*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013535:Suspensions; D013607:Tablets; D007093:Imidazoles; D011725:Pyridines; D000096926:Benzenesulfonamides
chemical_list: D058307:Receptors, Prostaglandin E, EP2 Subtype; D013453:Sulfonylurea Compounds; D013535:Suspensions; D013607:Tablets; C522837:grapiprant; D007093:Imidazoles; D011725:Pyridines; D000096926:Benzenesulfonamides