Pharmacokinetic-Pharmacodynamic Modeling of the Inhibitory Effects of Naproxen on the Time-Courses of Inflammatory Pain, Fever, and the Ex Vivo Synthesis of TXB2 and PGE2 in Rats

To quantify and compare the time-course and potency of the analgesic and antipyretic effects of naproxen in conjunction with the inhibition of PGE(2) and TXB2. Analgesia was investigated in a rat model with carrageenan-induced arthritis using a gait analysis method. Antipyretics were studied in a yeast-induced fever model using telemetrically recorded body temperature. Inhibition of TXB2 and PGE(2) synthesis was determined ex vivo. Pharmacokinetic profiles were obtained in satellite animals. Population PKPD modeling was used to analyze the data. The IC50 values (95% CI) of naproxen for analgesia (27 (0-130) mu M), antipyretics (40 (30-65) mu M) and inhibition of PGE(2) (13 (6-45) mu M) were in similar range, whereas inhibition of TXB2 (5 (4-8) mu M) was observed at lower concentrations. Variability in the behavioral measurement of analgesia was larger than for the other endpoints. The inhibition of fever by naproxen was followed by an increased rebound body temperature. Due to better sensitivity and similar drug-induced inhibition, the biomarker PGE(2) and the antipyretic effect would be suitable alternative endpoints to the analgesic effects for characterization and comparisons of potency and time-courses of drug candidates affecting the COX-2 pathway and to support human dose projections.