Plasma concentrations and therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse: pharmacokinetic/pharmacodynamic modelling

Abstract

The purpose of the present study was to establish in the horse the relationship between plasma concentration profiles of phenylbutazone (PBZ) and flunixin meglumine (FM) and their pharmacological effects in order to build a predictive pharmacokinetic/pharmacodynamic (PK/PD) model. In five horses, an experimental arthritis was induced by injecting Freund's adjuvant into a carpal joint. PBZ (4 mg/kg) and FM (1 mg/kg) were injected by the intravenous route as a single intravenous dose in two different trials. Five pharmacodynamic end-points were regularly measured after test article injection using standardized procedures: local skin temperature, stride length, the rest angle flexion and the maximal carpal flexion of the injured leg and circumference of the inflamed joint. Plasma drug concentrations and pharmacodynamic data were analysed according to an integrated PK/PD model; for the stride length, the PBZ EC50, i.e. the plasma concentration for which half the maximum effect could be obtained, was 3.6 +/- 2.2 micrograms/ml and the maximum potential effect was 10.7 +/- 9.4% above the control value. For FM, the corresponding values were 0.93 +/- 0.35 micrograms/ml and 16.3 +/- 4.6%. EC50 values for rest angle flexion and local skin temperature were similar to that obtained for stride length. Maximal carpal flexion was an unreliable end-point, and circumference of the joint did not display significant response to the drugs. Using these experimental parameters, a dose-effect relationship was simulated for both drugs; it was shown for PBZ that the model predicts an absence of effect for a 1 mg/kg dose and a maximum effect at about 2 mg/kg; at higher PBZ doses, the maximum effect was not modified, but its duration was increased from 8 h with a 2 mg/kg dose to about 24 h with an 8 mg/kg dose. For FM the model predicts that a dose of 0.5 mg/kg will be without significant effect, whereas a 1 mg/kg dose allows a nearly maximal effect with a return to the control value after a delay of 16 h. A 2 mg/kg dose allows the effect to be maintained for 24 h. It is concluded that PK/PD is a tool of potential value for the preclinical screening of a dosage regimen.

Efeito clínico do uso do parecoxib em modelo de sinovite induzida em pôneis

“…No exame clínico geral, foi determinada a freqüência cardíaca (FC), a freqüência respiratória (FR) e a temperatura retal (T). No exame clínico específico, foram avaliados os parâmetros de comprimento do passo (CP), ângulo do membro em repouso (AR), ângulo de flexão máxima da articulação rádiocarpiana (AFM), circunferência da mesma articulação em cm (CA) (Toutain et al, 1994;White et al, 1996), grau de efusão carpal (GE) (Owens et al, 1995) e grau de claudicação (GC) (Guide..., 1991). Para a mensuração do comprimento do passo, o casco do membro a ser avaliado foi marcado com tinta.…”

“…Para a mensuração do comprimento do passo, o casco do membro a ser avaliado foi marcado com tinta. Posteriormente, os pôneis foram conduzidos caminhando sobre uma superfície plana, e a distância (cm) entre as impressões do casco do membro afetado foi medida com auxílio de fita métrica (Toutain et al, 1994). A circunferência da articulação foi mensurada com fita métrica, usando como ponto de referência anatômico o osso carpo acessório (White et al, 2003).…”

“…A circunferência da articulação foi mensurada com fita métrica, usando como ponto de referência anatômico o osso carpo acessório (White et al, 2003). O ângulo da articulação em repouso e a flexão carpal máxima (até reação de dor) foram mensurados com um goniômetro (Toutain et al, 1994). O grau de efusão carpal foi avaliado subjetivamente e classificado de 1 a 4 conforme Owens et al (1995).…”

Pharmacokinetic/Pharmacodynamic (PK/PD) modeling of antipyretic effect of meloxicam: A preferential cyclooxygenase inhibitor in rat

“…Also, PK/PD modeling can be used to find out sensitive, efficacious and toxic dose. Only limited insights on in vivo NSAIDs pharmacokinetics and pharmacodynamics (Toutain et al, 1994(Toutain et al, , 2001Lees, 2003) are available, a few preclinical studies have been conducted to model blood or plasma concentration-time profiles. Especially for antipyretic activity, ibuprofen has been modeled in children to biophase concentration (Kelly et al, 1992;Brown et al, 1988) and to plasma concentration (Garg and Jusko, 1994) with indirect response models.…”

Palatability of flunixin and pharmacokinetics when administered to sheep through feed

“…Like other 46 NSAIDs, flunixin reduces inflammation by inhibiting cyclooxygenase and, in turn, decreasing 47 the production of prostaglandin (Cheng et al 1998b), an important inflammatory mediator. 48 Flunixin is known to be effective at relieving pain in various domesticated species such as horses 49 (Keegan et al 2008;Toutain et al 1994) and cattle (Currah et al 2009) and is currently 50 registered for use for these animals in the US, Europe and Australia (Feely et al 2002). Although 51 flunixin has also been shown to be effective for pain relief in sheep (Paull et al 2007; Welsh 52 1995), there are currently no registered NSAIDs in Australia for use in sheep.…”