Pharmacokinetic/pharmacodynamic modelling of NSAIDs in a model of reversible inflammation in the cat

Authors

  • Jerome M Giraudel,

    1. UMR 181 de Physiopathologie et Toxicologie Expérimentales INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des Capelles, BP 87614, 31076 Toulouse Cedex 3, France
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    • 3

      Current address: Novartis Sante Animale S.A.S., 14 Bd Richelieu – BP 430, F-92845 Rueil Malmaison cedex, France.

  • Armelle Diquelou,

    1. UMR 181 de Physiopathologie et Toxicologie Expérimentales INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des Capelles, BP 87614, 31076 Toulouse Cedex 3, France
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  • Valerie Laroute,

    1. UMR 181 de Physiopathologie et Toxicologie Expérimentales INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des Capelles, BP 87614, 31076 Toulouse Cedex 3, France
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  • Peter Lees,

    1. Department of Veterinary Basic Sciences, Royal Veterinary College, Hawkshead Campus, North Mymms, Hatfield, Hertfordshire AL9 7TA
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  • Pierre-Louis Toutain

    Corresponding author
    1. UMR 181 de Physiopathologie et Toxicologie Expérimentales INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des Capelles, BP 87614, 31076 Toulouse Cedex 3, France
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UMR 181 de Physiopathologie et Toxicologie Expérimentales INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des Capelles, BP 87614, 31076 Toulouse Cedex 3, France. E-mail: pl.toutain@envt.fr

Abstract

  • Data on the relationships between plasma concentration and analgesic and anti-inflammatory effects of NSAIDs are limited because most inflammation models do not permit pharmacokinetic/pharmacodynamic (PK/PD) modelling to be readily performed.

  • In this study, a kaolin-induced inflammation model in the cat was evaluated for pre-clinical characterization of the pharmacodynamic profiles of NSAIDs (determination of efficacy, potency, sensitivity (that is the slope of the concentration–effect relationship) and duration of drug response), using meloxicam as a probe article.

  • Indirect response PK/PD models described the time course and magnitude of responses produced by 0.3 mg kg−1 meloxicam administered subcutaneously. For endpoints for which spontaneous recovery from inflammation was superimposed on drug response, a PK/PD model with a time-dependent Kin was used to allow for the spontaneous changes of the inflammation with time.

  • The selected endpoints were suitable for studying simultaneously the analgesic, anti-inflammatory and antipyretic effects of meloxicam, allowing comparison of relative potencies for these effects. Mean±s.d. IC50 or EC50 values (ng ml−1) were 777±124 (body temperature), 841±187 (locomotion variable), 883±215 (pain score), 911±189 (lameness score) and 1298±449 (skin temperature difference). Corresponding mean times±s.d. of peak responses (h) were 5.6±1.3, 8.6±3.8, 5.2±5.0, 5.6±3.7 and 4.3±2.4, respectively.

  • As the pharmacokinetic profiles of meloxicam in cats and humans are similar, simulations of several dosage regimens in the cat provided a pre-clinical basis, illustrating the value of the cat model for predicting a clinical dose regimen for evaluation in man. The predicted loading doses (mg kg−1) of meloxicam in the cat producing 70% of the maximum attainable responses were 0.29 (body temperature), 0.32 (lameness score), 0.33 (overall locomotion variable), 0.36 (pain score) and 0.50 (skin temperature difference). The values are similar to or somewhat greater than the clinically recommended doses both in cats (0.3 mg kg−1) and humans (7.5–15 mg, that is, between 0.1 and 0.3 mg kg−1).

  • These findings indicate the potential value of the cat as a laboratory model, and of a PK/PD modelling approach in assisting NSAID development programs in animals and humans.

British Journal of Pharmacology (2005) 146, 642–653. doi:10.1038/sj.bjp.0706372

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