Modeling and Simulation to Support Dose Selection and Clinical Development of SC-75416, a Selective COX-2 Inhibitor for the Treatment of Acute and Chronic Pain

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Abstract

Pharmacokinetic/pharmacodynamic (PK/PD) models were developed and clinical trial simulations were conducted to recommend a study design to test the hypothesis that a dose of SC-75416, a selective cyclooxygenase-2 inhibitor, can be identified that achieves superior pain relief (PR) compared to 400mg ibuprofen in a post-oral surgery pain model. PK/PD models were developed for SC-75416, rofecoxib, valdecoxib, and ibuprofen relating plasma concentrations to PR scores using a nonlinear logistic-normal model. Clinical trial simulations conducted using these models suggested that 360mg SC-75416 could achieve superior PR compared to 400mg ibuprofen. A placebo- and positive-controlled parallel-group post-oral surgery pain study was conducted evaluating placebo, 60, 180, and 360mg SC-75416 oral solution, and 400mg ibuprofen. The study results confirmed the hypothesis that 360mg SC-75416 achieved superior PR relative to 400mg ibuprofen (ΔTOTPAR6=3.3,P<0.05) and demonstrated the predictive performance of the PK/PD models.

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