Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors.
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.
Huntjens
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DR
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Danhof
M
M
Della Pasqua
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OE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D008565:Membrane Proteins; D010146:Pain / Q000097:blood / Q000188:drug therapy; D010147:Pain Measurement / Q000379:methods; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood*; D015398:Signal Transduction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases