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Methods: Two separate, complete three-way crossover studies were conducted. In both studies, eleven patients received 325 mg of aspirin, either 220 mg or 440mg of naproxen sodium and co-administration of both naproxen and aspirin. Whole blood platelet aggregometry was utilized to measure the aggregatory response of platelets in the presence of both collagen (1µg/ml) and arachidonic acid (0.5 mM) at 0, 2, 4, 8, 12, 24, 48 and 72 hours after drug administration. Pharmacokinetic parameters from the literature were utilized to simulate expected concentrations of drug within each subject. Pharmacodynamic modeling of the aggregatory response was analyzed using ADAPT V maximization likelihood expectation maximization (MLEM) algorithm using an additive error model.
Results:
Inhibition of platelet aggregation after administration of aspirin occurred at 2 h and platelet function returned to baseline between 72-96 h. Following administration of naproxen alone, inhibition of platelet aggregation occurred at 2 h and platelet function returned to baseline between 8-24 h. Platelet aggregation after concomitant administration of aspirin and naproxen occurred in 2 h and returned to baseline function between 12-24 h. The final pharmacodynamic model was based the turnover of COX-1(kout) and integrates the irreversible effect of aspirin (K) with the reversible effect of naproxen binding on COX-1 activity. Fitted parameter values for K (0.102 h-1(10.3% RSE)) and kout (0.022 (17.1%RSE)), with the standard deviation of inter-individual variability equal to 0.0093(mg/L)-1•h-1 and 0.006 h-1 and respectively, were found with the current pharmacodynamic model.
Conclusion: A mechanism based-pharmacodynamic model has been applied to a concomitant dose of naproxen and aspirin. This study suggests that naproxen has an inhibitory effect on the time-course of aspirin based anti-platelet effect.