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

Abstract

1 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. 2 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. 3 Indirect response PK/PD models described the time course and magnitude of responses produced by 0.3 mg kg À1 meloxicam administered subcutaneously. For endpoints for which spontaneous recovery from inflammation was superimposed on drug response, a PK/PD model with a timedependent K in was used to allow for the spontaneous changes of the inflammation with time. 4 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. ) and humans (7.5-15 mg, that is, between 0.1 and 0.3 mg kg À1). 6 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.

Paw Inflammation Model in Dogs for Preclinical Pharmacokinetic/Pharmacodynamic Investigations of Nonsteroidal Anti-Inflammatory Drugs

“…This would arise especially if the tested dose was too low. Using our PK/PD model, we estimated the meloxicam potency for different end points of clinical relevance, and we also confirmed the general statement that potency is usually similar between species (Levy, 1993;Busch et al, 1998), because the present results are very similar to those obtained in cats using the same model (Giraudel et al, 2005a) and in man (Davies and Skjodt, 1999). Because the meloxicam kinetic parameters (clearance and half-life) and meloxicam potency are very similar in dogs and man, the present canine model should be able to predict a relevant dosage regimen in man.…”

“…The PK/PD approach itself can be considered as a refinement of a dose titration allowing a reduction in the required number of animals to establish a full dosage regimen (dose and dosing interval), but to achieve our ultimate goal of rehabilitating experimental animals, it was necessary to develop and validate a new reversible inflammation model in dogs. Such a model was developed recently in cats (Giraudel et al, 2005a). It consisted of administering kaolin (an inert foreign body) as a phlogistic agent in the paw.…”

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

“…Due to the possibility of repeated measurements and increased reproducibility and sensitivity, PGE 2 could be a suitable alternative endpoint for investigations and comparisons of the time-course and potency of various drug candidates [23] . Several reports have shown the integrated PK-PD modeling of NSAIDs using hyperthermia, hyperalgesia, edema or PGE 2 as pharmacological endpoints [5,11,23] , but little attention has been paid to the impact of the disease status on drug effects [16] . The aim of this study was to characterize the PK-PD modeling of diclofenac in normal and FCA-induced arthritic rats using PGE 2 as a pharmacological endpoint.…”

“…The prediction of safety and long-term efficacy has become the main challenge in the evaluation of NSAIDs for the treatment of pain in chronic inflammatory conditions. Pharmacokinetic-pharmacodynamic (PK-PD) modeling represents a powerful tool to quantitatively describe the pharmacokinetic, pharmacodynamic and systemrelated processes [5] . Several attempts have been made to illustrate the relationship between the plasma concentrationtime profiles of NSAIDs and the pharmacological activity of these drugs using two types of traditional pharmacological endpoints: (i) those exploring the inflammatory response and having a mechanistic interest, such as central and local hyperthermia (body and skin temperature), hyperalgesia (pain score) and edema (paw volume) and (ii) the hybrid endpoints that have direct clinical relevance and reflect both the pain and functional impairments [2,[6][7][8][9][10][11] .…”

Coptisine from Coptis chinensis inhibits production of inflammatory mediators in lipopolysaccharide-stimulated RAW 264.7 murine macrophage cells

“…**P o 0.01 compared with the LPS group. Hongkong, China) prior to the drug intravenous injection and monitored at 0.5 h intervals for 4 h (Giraudel et al, 2005). The data were recorded thrice at each time point and the difference between control paw and inflamed paw was analyzed.…”