Pharmacokinetics and estimated bioavailability of grapiprant, a novel selective prostaglandin E₂ receptor antagonist, after oral administration in fasted and fed dogs

Abstract

AIMS: To assess the effect of food intake on the pharmacokinetics of grapiprant administered orally at 2 mg/kg, and to estimate its oral bioavailability in dogs.

METHODS: Eight healthy female Labrador Retriever dogs, aged 4–10 years were used. In the initial trial two dogs were administered a 0.5 mg/kg I/V bolus of grapiprant dissolved in ethanol. In the second trial, six dogs were assigned to two treatment groups, using a randomised cross-over design, and received 2 mg/kg of grapiprant orally, as pure powder, after fasting for 12 hours or after being fed. Blood samples were collected at preassigned times up to 36 hours after administration, and concentrations of grapiprant in plasma determined using validated high performance liquid chromatography.

RESULTS: After I/V administration in the two dogs the terminal half life was 5.30 and 6.06 hours, clearance was 444 and 476 mL/hours/kg, and volume of distribution was 3,642 and 3,883 mL/kg. Compared with fasted dogs, oral administration in fed dogs resulted in reduced median peak concentrations in plasma (1,598 vs. 614 ng/mL) and delayed median time of peak concentration (1.0 vs. 3.0 hours). The estimated bioavailability in fasted and fed dogs was 111.9 and 59.1%, respectively. Concentrations of grapiprant in plasma following oral administration, in either fed or fasted dogs, remained higher than 164 ng/mL for up to 6 hours. This concentration has been estimated to be the minimal effective concentration required to control pain in dogs.

CONCLUSION AND RELEVANCE: Oral administration of 2 mg/kg grapiprant in fed and fasted dogs resulted in different pharmacokinetics of the drug, but did not influence the length of time when concentrations in plasma exceeded theoretical effective concentrations. Further studies are necessary to verify these findings using pharmacokinetic-pharmacodynamic studies and in clinical subjects.

KEY WORDS:

• Bioavailability
• dogs
• EP₄ receptor antagonist
• grapiprant
• pharmacokinetics

Acknowledgements

Authors thanks Dr S. Aupanun and Miss B. Nassi, for their technical assistance.

ORCiD

B Łebkowska-Wieruszewska http://orcid.org/0000-0002-1569-0599

G Barsotti http://orcid.org/0000-0002-6529-3348

A Lisowski http://orcid.org/0000-0003-1463-9908

A Gazzano http://orcid.org/0000-0001-9649-2027

M Giorgi http://orcid.org/0000-0003-3657-4703

Notes

*Non-peer-reviewed

Additional information

Funding

This work was supported by athenaeum funds (University of Pisa). Any external funding did not support the preparation of manuscript.