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Tolerance and Pharmacokinetics of Galliprant™ Administered Orally to Collies Homozygous for MDR1‐1Δ

The objectives of the study were to evaluate the pharmacokinetics and tolerance of grapiprant, a substrate of the human P‐gp transporter, in collies homozygous for MDR1‐1Δ when administered at the labeled dosage of 2 mg/kg once daily for 28 days. Twelve collie dogs with homozygous for MDR1‐1Δ genoty...

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Detalles Bibliográficos
Autores principales: Heit, Mark C., Mealey, Katrina L., King, Stephen B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9292342/
https://www.ncbi.nlm.nih.gov/pubmed/34219249
http://dx.doi.org/10.1111/jvp.12984
Descripción
Sumario:The objectives of the study were to evaluate the pharmacokinetics and tolerance of grapiprant, a substrate of the human P‐gp transporter, in collies homozygous for MDR1‐1Δ when administered at the labeled dosage of 2 mg/kg once daily for 28 days. Twelve collie dogs with homozygous for MDR1‐1Δ genotype from a commercial colony were used in the study, eight in the treated group and four as placebo‐treated controls. The only treatment‐related clinical sign was self‐limiting vomiting (in 2/8 treated animals) and the only treatment‐related clinical pathological changes seen were a slight decrease in serum albumin in one dog (2.6 g/dL; reference 2.7 to 3.9 g/dL) and total protein (5.1 g/dL; reference 5.5 to 7.7 g/dL). Absorption of grapiprant was rapid with a median T(max) of 1 h, C(max) of 5.2 μg/mL, AUC(0‐24) of 17.3 ± 7.1 h(*)μg/mL and median terminal t½ of 4.3 h after the first dose. To determine whether MDR1‐1Δ animals handle grapiprant differently from normal dogs, a population pharmacokinetic analysis was performed utilizing data from the collies and historical beagle data. Volume of the peripheral compartment of collies was estimated to be 45% that of beagles, and clearance from the central compartment was 71% less in collies than in beagles. Self‐liming vomiting events occurred at a numerically higher rate (2/8; 25%) in this group of P‐gp‐deficient dogs than seen in a clinical study (17%) composed of various dog breeds but limited numbers in this PK study make comparisons difficult. Grapiprant was otherwise well tolerated in collies homozygous for MDR1‐1Δ despite increased drug exposure compared to dogs without this mutation.