Dheeraj Gopu, Harish Kaushik K, Gomathi P
Objective: To establish a suitable Pharmacokinetic / Pharmacodynamic (PK/PD) model for the meloxicams anti-inflammatory activity for predictions about efficacy, potency and sensitivity by using a complex indirect response model in the rat, where carrageenin used as a inflammogen.
Methods: The rats were divided into different groups and received 1, 3, 7 and 10 mg/kg of meloxicam, after sub-plantar injection of carrageenin to the right hind paw. The plasma concentrations of meloxicam were determined by RP-HPLC-UV method and pharmacodynamics (paw edema volume) measured by plethesmography.
PK/PD model: Before injection of carrageenin, basal inflammatory mediators synthesis (PEI2) is maintained by physiological mechanism which is described by a constant rate synthesis (Ksyn) and a first order degradation (Kout). Ksyn is computed by equation Ksyn = E0. Kout. After injection of carrageenin, the additional inflammatory 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.
Results: The PK parameters showed dose proportionality, with a Vd, 2101, 3761, 4754and 5321 mL/kg, CL, 774, 1738, 1872 and 1913mL/hr/kg, Cmax, 175, 290, 544 and 731ng/mL. Indirect response PD model (inhibitory Emax model), estimated KIN 1.24, 1.96, 1.95 and 1.89 1/hr, Kout 0.012, 0.019, 0.021 and 0.025 1/hr, Ksyn 0.0032, 0.0039, 0.0038, and 0.0026 h, estimates for IC50 (concentration of meloxicam in plasama eliciting half of maximum inhibition of IR(t) or KIN were 418.5, 565.91, 832.96 and 1482.7 ng/mL of group II, group III, group IV and group V respectively.