PLASMA-CONCENTRATIONS AND THERAPEUTIC EFFICACY OF PHENYLBUTAZONE AND FLUNIXIN MEGLUMINE IN THE HORSE - PHARMACOKINETIC PHARMACODYNAMIC MODELING/

The purpose of the present study was to establish in the horse the rel ationship between plasma concentration profiles of phenylbutazone (PBZ ) and flunixin meglumine (FM) and their pharmacological effects in ord er to build a predictive pharmacokinetic/pharmacodynamic (PK/PD) model , In five horses, an experimental arthritis was induced by injecting F reund's adjuvant into a carpal joint. PBZ (4 mg/kg) and FM (1 mg/kg) w ere injected by the intravenous route as a single intravenous dose in two different trials. Five pharmacodynamic endpoints were regularly me asured after test article injection using standardized procedures: loc al skin temperature, stride length, the rest angle flexion and the max imal carpal flexion of the injured leg and circumference of the inflam ed joint, Plasma drug concentrations and pharmacodynamic data were ana lysed according to an integrated PK/PD model; for the stride length, t he PBZ EC(50), i.e, the plasma concentration for which half the maximu m effect could be obtained, was 3.6 +/- 2.2 mu g/ml and the maximum po tential effect was 10.7 +/- 9.4% above the control value, For FM, the corresponding values were 0.93 +/- 0.35 mu g/ml and 16.3 +/- 4.6%. EC( 50) values for rest angle flexion and local skin temperature were simi lar to that obtained for stride length, Maximal carpal flexion was an unreliable end-point, and circumference of the joint did not display s ignificant 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 do se and a maximum effect at about 2 mg/kg; at higher PBZ doses, the max imum 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 mod el predicts that a dose of 0.5 mg/kg will be without significant effec t, 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 too l of potential value for the preclinical screening of a dosage regimen .