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 modelli...

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Bibliographic Details
Published in:European journal of pain 2010-03, Vol.14 (3), p.227.e1-227.e10
Main Authors: Huntjens, Dymphy R.H, Spalding, David J.M, Danhof, Meindert, Della Pasqua, Oscar E
Format: Article
Language:English
Subjects:
Anesthesia & Perioperative Care
Animals
Biomarkers
Dinoprostone - metabolism
Dose-Response Relationship, Drug
Freund's Adjuvant - pharmacology
Freund's complete adjuvant
Inflammation - chemically induced
Inflammation - metabolism
Naproxen
Naproxen - pharmacokinetics
NSAIDs
Pain Medicine
PKPD modelling
Rats
Rats, Sprague-Dawley
Thromboxane B2 - metabolism
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Summary: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 (10 mg/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 ± 677 ng / ml ( mean ± SD ) , whilst IC 50 values for TXB 2 inhibition increased from 1180 ± 323 to 3360 ± 453 ng / 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.
ISSN:1090-3801
1532-2149
DOI:10.1016/j.ejpain.2009.05.017