Impact of chronic inflammation on the pharmacokinetic-pharmacodynamic relationship of naproxen.

ABSTRACT

OBJECTIVES: The use of biomarkers for predicting the clinical doses of analgesic drugs relies on the understanding of the relationship between drug exposure and response under disease conditions. In this study, we demonstrate the relevance of such a relationship for COX-inhibitors by modelling the effect of naproxen on prostaglandin E2 (PGE(2)) and thromboxane B2 (TXB(2)) in a chronic inflammation model in rats. METHODS: Rats were treated with Freund's complete adjuvant (FCA) by intraplantar injection. On post-inoculation days (PID) 7-21, animals received single or chronic (qd until day 21) doses of naproxen (10mg/kg). Blood samples were collected at various intervals after dosing to characterise naproxen pharmacokinetics and its effects on PGE(2) and TXB(2) production. PK-PD modelling was performed using nonlinear mixed effects in NONMEM. RESULTS: The inhibition of PGE(2) and TXB(2) could be described by a sigmoid E(max) model. A decrease in the potency estimates of both biomarkers was observed under chronic inflammation, as compared to healthy animals. IC(50) values for PGE(2) inhibition showed a shift from 2840+/-510 to 4000+/-677ng/ml(mean+/-SD), whilst IC(50) values for TXB(2) inhibition increased from 1180+/-323 to 3360+/-453ng/ml in healthy and FCA-inoculated animals, respectively. CONCLUSIONS: Our results show that chronic inflammation causes a significant change in the potency estimates for COX-inhibition. These findings illustrate the implications of pathophysiological processes on pharmacodynamics and consequently on the required exposure levels for achieving response during chronic treatment.