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Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation

Pelligand, L; King, J N; Hormazabal, V; Toutain, P L; Elliott, J; Lees, P

Authors

L Pelligand

J N King

V Hormazabal

P L Toutain

J Elliott

P Lees



Abstract

Robenacoxib and ketoprofen are acidic nonsteroidal anti‐inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half‐lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three‐period cross‐over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX‐1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E2 concentrations (measuring COX‐2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX‐1 and COX‐2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half‐life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half‐life = 1.13 h). Exudate elimination half‐lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivoIC50COX‐1/IC50COX‐2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX‐2 inhibition in exudate, despite short half‐lives in blood.

Citation

Pelligand, L., King, J. N., Hormazabal, V., Toutain, P. L., Elliott, J., & Lees, P. (2014). Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation. Journal of Veterinary Pharmacology and Therapeutics, 37(4), 354-366. https://doi.org/10.1111/jvp.12107

Journal Article Type Article
Acceptance Date Jan 2, 2014
Publication Date Mar 15, 2014
Deposit Date Nov 11, 2014
Publicly Available Date Mar 29, 2024
Journal JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS
Print ISSN 0140-7783
Publisher American Academy of Veterinary Pharmacology and Therapeutics
Peer Reviewed Peer Reviewed
Volume 37
Issue 4
Pages 354-366
DOI https://doi.org/10.1111/jvp.12107
Public URL https://rvc-repository.worktribe.com/output/1405840