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Impact of chronic inflammation on the pharmacokinetic–pharmacodynamic relationship of naproxen
Author(s) -
Huntjens Dymphy R.H.,
Spalding David J.M.,
Danhof Meindert,
Pasqua Oscar E.
Publication year - 2010
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1016/j.ejpain.2009.05.017
Subject(s) - naproxen , pharmacodynamics , nonmem , medicine , pharmacology , inflammation , pharmacokinetics , potency , thromboxane b2 , immunology , chemistry , platelet , pathology , in vitro , biochemistry , alternative medicine
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 and thromboxane B2 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 (10 mg/kg). Blood samples were collected at various intervals after dosing to characterise naproxen pharmacokinetics and its effects on and production. PK‐PD modelling was performed using nonlinear mixed effects in NONMEM. Results: The inhibition of and could be described by a sigmoid model. A decrease in the potency estimates of both biomarkers was observed under chronic inflammation, as compared to healthy animals. values for inhibition showed a shift from to , whilst values for inhibition increased from to 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.