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

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. Keywords: PK/PD modelling, NSAID, cat, reversible inflammation, meloxicam, kaolin Introduction In vivo pharmacokinetic/pharmacodynamic (PK/PD) modelling is increasingly accepted as a powerful approach for determining pharmacodynamic parameters, and thus for selecting effective and safe dosage regimens for clinical use. However, despite a large body of scientific literature on nonsteroidal anti-inflammatory drug (NSAID) pharmacokinetics and pharmacodynamics, relatively few pre-clinical studies have attempted to model blood or plasma concentration–time profiles with the time course of NSAID effects (Toutain et al., 1994; Granados-Soto et al., 1995; Landoni & Lees, 1995; Landoni et al., 1995; Torres-Lopez et al., 1997; Flores-Murrieta et al., 1998; Josa et al., 2001; Toutain et al., 2001; Lees, 2003). PK/PD modelling approaches permit the in vivo determination of numerical values for the three pivotal pharmacodynamic parameters of a drug, namely efficacy, potency and sensitivity (that is the slope of the concentration–effect relationship). These parameters allow prediction of the magnitude and time course of drug effect for any formulation, route of administration or dosage regimen, provided corresponding pharmacokinetic data are available (Toutain et al., 2001; Toutain, 2002). In addition, if drug plasma concentrations required to produce a given degree of pharmacological effect are similar in animals and man (Levy, 1993), PK/PD modelling in a non-human species offers a valuable approach to dosage regimen prediction for human use. Currently, the application of PK/PD principles to determination of the pre-clinical profile of NSAIDs is limited by the availability of validated animal models and the inability of existing models to provide clinically relevant endpoints of drug response. Most of the inflammation models that have been developed in rodents and dogs (e.g. carrageenan-induced paw oedema, uric acid-induced arthritis) are too short-lasting to permit an accurate determination of the complete drug concentration–effect relationship. This partially accounts for the fact that dose-titration approaches, based on pre-challenge NSAID administration, have been preferred. A further drawback of rodent models is that they do not readily permit measurement of clinically relevant endpoints (e.g. lameness scoring). On the other hand, irritants such as Freund's complete adjuvant result in a sustained and relatively stable inflammatory response in the dog (Botrel et al., 1994; Toutain et al., 1994, 2001), allowing measurement of relevant and sensitive endpoints (e.g. vertical force applied by the hind limb, lameness score, etc.). However, for ethical reasons, the use of this irreversible inflammation model may be questioned. Consequently, an acceptable inflammation model should be neither too severe nor irreversible, but should be sufficiently long lasting to allow an accurate evaluation of the three main responses to NSAIDs, namely their anti-inflammatory, antipyretic and analgesic effects. The model should also be developed in a medium-sized species (e.g. dog, cat) to enable both collection of clinically relevant endpoints and sequential blood sampling for determination of drug concentration in blood/plasma–time profiles. Recent studies by our group have shown that subcutaneous (s.c.) injection of kaolin in a cat's paw produces a well-defined, reproducible and reversible inflammatory response (Giraudel et al., 2005a). The signs of inflammation induced with 500 mg kaolin were relatively constant between 2 and 4 days after kaolin injection, allowing administration of the NSAID on day 2. This model also incorporated (a) quantitative measurement of objective endpoints relevant to therapeutic efficacy and (b) the possibility of sequential blood sampling. Based on statistical (reproducibility and accuracy of the measurement) and biological significance, it was anticipated that body temperature, gait scoring, times for performance of locomotion tests and possibly paw volume and skin temperature might be suitable for PK/PD studies (Giraudel et al., 2005a). Moreover, the model was found to be suitable for studying simultaneously the analgesic, anti-inflammatory and antipyretic effects of NSAIDs. This is of considerable interest, because it is possible and even likely that concentration–effect relationships will differ for each of these effects. Whereas analgesia seems to occur in a concentration-dependent manner, anti-inflammatory effect is more closely correlated with the time of exposure to a given drug (Walker, 1995). Such differences and the characteristics of the dose–effect relationship (efficacy, potency and slope, for example, ‘all or nothing' response compared with a progressive graded response) can be readily determined using a pre-clinical PK/PD modelling approach. The aim of the current study was to assess the value of the feline paw inflammation model for pre-clinical characterization of the full pharmacological profile of a NSAID and then to apply it to prediction of dosage regimens for evaluation in other animal species and in man. Meloxicam was selected as a reference NSAID, because it has been used extensively as a therapeutic agent in both animals and humans, and its dosage regimen is now well established both in man and the cat (Engelhardt, 1996; Turck et al., 1996; Busch et al., 1998; Slingsby & Waterman-Pearson, 2000; Lascelles et al., 2001).