Single-Dose Pharmacokinetics of Grapiprant in Rhesus Macaques (Macaca mulatta)

Grapiprant belongs to the newer piprant class of nonsteroidal anti-inflammatory drugs (NSAIDs) and is FDA approved for treatment of osteoarthritis in dogs. The compounds act as an antagonist at the prostaglandin E₂ EP4 receptor and is therefore also noncyclooxygenase inhibiting. This mechanism of action reduces the potential for adverse side effects associated with cyclooxygenase inhibition and makes it a promising drug for long-term use in nonhuman primates (NHPs) with chronic inflammatory conditions. In this study, we sought to establish pharmacokinetic parameters of an oral oil suspension of grapiprant in healthy, fasted male and female rhesus macaques (Macaca mulatta) with a single oral dose of 2 mg/kg, the current FDA-approved dose in dogs. Blood was collected at time 0 (baseline) and at 9 additional time points (0.25, 0.5, 1, 2, 4, 8, 12, 24, and 48 h) after dosing. Grapiprant plasma concentration was quantified using liquid chromatography–tandem mass spectrometry. Our data show that rhesus macaques absorb grapiprant more slowly (T_max = 2 h for all subjects) and at a lower level (C_max = 23.8 ± 19.6 ng/mL, AUC_last = 77.5 ± 42.9 ng·h/mL) than published values in dogs. No significant difference was noted in pharmacokinetic parameters between males and females; however, females showed more variability in pharmacokinetic parameters than did males. Significant age effects were not observed, although a positive correlation between C_max and AUC_last with age in males was noted. Our data suggest that higher doses should be explored in rhesus macaques, with a need for further investigation into the pharmacodynamics of grapiprant to establish an efficacious therapeutic dose in this species and other NHPs.