Pharmacokinetic/pharmacodynamic modeling of antipyretic and anti-inflammatory effects of naproxen in the rat

Pharmacokinetic/pharmacodynamic modeling was used to characterize the antip yretic and anti-inflammatory effects of naproxen in rats. An indirect respo nse model was used to describe the antipyretic effects of naproxen after sh ort intravenous infusions. The model assumes that basal temperature (T-a) i s maintained by the balance of fever mediators given by a constant (zero or der) rate of synthesis (K-syn), and a first order rate of degradation (K-ou t). After an intraperitoneal injection of lipopolysaccharide, the change in T-a was modeled assuming an increase in fever mediators described as an in put rate function [IR(t)] estimated nonparametrically. An inhibitory E-max model adequately described the inhibition of IR(t) by naproxen. A more comp lex model was used to describe the anti-inflammatory response of oral napro xen in the carrageenin-induced edema model. Before carrageenin injection, p hysiological conditions are maintained by a balance of inflammation mediato rs given by K-syn and K-out (see above). After carrageenin injection, the a dditional synthesis of mediators is described by IR(t) (see above). Such me diators induced an inflammatory process, which is governed by a first order rate constant (K-IN) that can be inhibited by the presence of naproxen in plasma. The sigmoidal E-max model also well described the inhibition of K-I N by naproxen. Estimates for IC50 [concentration of naproxen in plasma elic iting half of maximum inhibition of IR(t) or K-IN] were 4.24 and 4.13 mg/ml , for the antipyretic and anti-inflammatory effects, respectively.