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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
Author(s) -
Kowalski KG,
Olson S,
Remmers AE,
Hutmacher MM
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100374
Subject(s) - valdecoxib , ibuprofen , rofecoxib , placebo , medicine , cyclooxygenase , pharmacodynamics , pharmacokinetics , clinical trial , cox 2 inhibitor , anesthesia , pharmacology , clinical pharmacology , chemistry , biochemistry , alternative medicine , pathology , enzyme
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 400 mg 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 360 mg SC‐75416 could achieve superior PR compared to 400 mg ibuprofen. A placebo‐ and positive‐controlled parallel‐group post–oral surgery pain study was conducted evaluating placebo, 60, 180, and 360 mg SC‐75416 oral solution, and 400 mg ibuprofen. The study results confirmed the hypothesis that 360 mg SC‐75416 achieved superior PR relative to 400 mg ibuprofen (ΔTOTPAR6=3.3, P <0.05) and demonstrated the predictive performance of the PK/PD models. Clinical Pharmacology & Therapeutics (2008); 83 , 6, 857–866 doi: 10.1038/sj.clpt.6100374