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Rheumatology Advance Access first published online on April 26, 2005
This version published online on April 28, 2005
Rheumatology, doi:10.1093/rheumatology/keh627
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received October 29, 2004
Accepted March 1, 2005

Review

Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors

D. R. H. Huntjens 1, M. Danhof 1, and O. E. Della Pasqua 2*

1 Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9503, 2300 RA, Leiden, The Netherlands
2 Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; GlaxoSmithKline, Clinical Pharmacology and Discovery Medicine, UK

* To whom correspondence should be addressed.
O. E. Della Pasqua, E-mail: odp72514{at}gsk.com


  Abstract

The mechanism by which COX inhibitors exert their analgesic effect is well established. However, data show no direct correlation between drug concentrations in plasma and the analgesic or adverse effects in chronic inflammatory conditions. This represents a major problem in the development of COX inhibitors, since it is difficult to predict the appropriate dosing regimen for the treatment of chronic inflammatory pain, based upon information from pre-clinical studies and eventually early clinical studies. The factors that determine response in inflammatory pain must be understood in order to make predictions about the time course of the analgesic effect. In this review the determinants of drug response and their variability will be discussed: physicochemical properties, pharmacokinetics (PK), pathophysiology and disease progression.

From a mechanistic point of view, endogenous mediators of inflammation might be used as a biomarker for the analgesic effect and safety assessment. Such a biomarker can be an intermediate step between drug exposure and response. In addition, its concentration-effect relationship could be characterized by pharmacokinetic-pharmacodynamic (PK/PD) modelling. Indeed, recent investigations have shown that COX-2 inhibition, as determined by modelling of prostaglandin E2 (PGE2) levels in the whole blood assay in vitro can be used as a marker to predict drug effects (analgesia) in humans. A model-derived parameter, IC80, (total and unbound) was found to correlate directly with the analgesic plasma concentration of different COX inhibitors varying in enzyme selectivity. These findings indicate that PGE2 and thromboxane B2 inhibition can be used to predict and select efficacious doses in humans.

This is a corrected version of that already published. In the previous version, some of the author's corrections to the first proof had not been made. These corrections were located in the footnote to Table 2, two of the entries in Table 3, the legend to Figure 7, and references 6 and 61. The publisher would like to apologise for this error.
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