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

摘要

The main purpose of this study was to predict the efficacy, potency and sensitivity of meloxicam (a preferential cyclooxygenase-2 (COX-2) inhibitor) antipyretic effect by using a simple indirect response model in rat, evaluated by Brewer’s yeast induced model. The rats received 1, 3, 7 and 10 mg/kg of meloxicam, after?subcutaneous?(sc) injection of Brewer’s yeast. The plasma concentrations of meloxicam were determined by high performance liquid chromatography-ultraviolet (HPLC-UV) method. Rectal temperature (Ta) was measured for the assessment of the pharmacodynamic (PD) of the meloxicam. Before injection of yeast, basal fever mediator’s synthesis (prostaglandin E2;?PGE2) is maintained by physiological mechanism to regulate body temperature which is described by a constant rate synthesis (Ksyn) and a first order degradation of Kout. Ksyn?is calculated by the equation, Ksyn?= E0?Kout, where E0?is the baseline body temperature. After injection of yeast, the additional fever mediators’ synthesis is regulated by input rate (IR (t)). This process is governed by a first order rate constant (KIN), which can be inhibited by meloxicam. The pharmacokinetic (PK) parameters showed dose proportionality, with a Vd (4124.52, 4236.73, 4657.15, and 5912.1 ml/kg), CL (78.55, 149.25, 1313.57, and 1519.41 ml/h/kg), and Cmax (84.72, 258.29, 547.74, and 617.85 ng/ml). Indirect response PD model (inhibitory Emax?model), estimated KIN?(1.43, 0.63, 0.51, and 0.42 1/h), Kout?(0.005, 0.008, 0.015, and 0.028 1/h), and Ksyn?(0.29, 0.42, 0.076, and 0.03 h); estimates for IC50?(concentration of meloxicam in plasma eliciting half of maximum inhibition of IR(t) or KIN) were 146.19, 379.51, 645.05, and 676.44 ng/ml of 1, 3, 7 and 10 mg/kg dose received by groups, respectively. This model appropriately describes the time course of pharmacological response to meloxicam to various doses, in terms of its mechanism of action and pharmacokinetics.