Dymphy Huntjens, Magret Blom-Roosemalen, David Spalding, Meindert Danhof and Oscar Della Pasqua
LACDR/ Pharmacology
Introduction: Cyclo-oxygenase (COX) inhibitors are widely used to treat acute inflammation and pain. They act by inhibiting the activity of the COX enzyme, and consequently the formation of prostaglandins and thromboxanes. The enzyme exists in two isoforms, COX-1 and COX-2 and it is now widely believed that inhibition of COX-1 accounts for the side effects, whilst inhibition of COX-2 accounts for the therapeutic benefits. No direct correlation is observed between the pharmacokinetics (PK) in plasma and analgesic effects of COX-inhibitors in either humans or animals. A biomarker, reflecting a process on the inflammatory cascade, may enable the characterisation of this nonlinear relationship. Such a biomarker may also allow extrapolation and prediction from animals to humans.
In this study, the effects of naproxen, a non-selective COX-inhibitor, on PGE2 inhibition, a biomarker for the selective effects on COX-2, were investigated in vitro in rats and healthy volunteers. Results were compared to in vivo concentration-PGE2 inhibition relationship of naproxen in rats.
Methods: In vitro study: In rats, blood samples were collected from the tail vein, wheras in healthy volunteers, blood samples were collected from the volar forearm. Samples were incubated with spiked concentrations of naproxen. PGE2 concentrations were measured by Enzyme Immuno Assay (EIA). In addition, protein binding of naproxen was measured by ultracentrifugation. In vivo study: Naproxen was administered intraperitoneally (2.5 and 25 mg/kg) to male rats. At regular time-intervals, blood was collected from the tail vein to determine PK in plasma and systemic PGE2 levels.
Results: The naproxen concentration-PGE2 inhibition relationship in vitro in rats and humans was modelled with the Hill model using non-linear mixed effect modelling. Inter-individual parameters were assigned to Imax, I0, IC50 and Hill coefficient. Naproxen was more potent in rats as compared to humans. No significant differences in Hill, I0 and Imax were found between rats and humans, which indicates identical mechanism of COX-2 inhibition of naproxen in rats and humans.
Free fraction ranged from 1.9±0.2-12.9±1.3 % in rats, versus 0.4±0.3-1.8±0.4 % in humans. Differences in potency of naproxen between rats and humans could be explained by differences in protein binding.
Dose dependent PGE2 inhibition was observed in vivo after naproxen administration. These findings show direct correlation with in vitro data indicating the predictive value of the latter.
Conclusions: Model-derived parameters from PGE2 inhibition enables the characterisation of drug-effects in animals and humans. Protein binding accounts for differences in potency between rats and humans. In vitro findings of naproxen PGE2 inhibition correlate to in vivo data.
Reference: PAGE 12 (2003) Abstr 449 [www.page-meeting.org/?abstract=449]
Poster: poster