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.
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 (DeltaTOTPAR6=3.3, P<0.05) and demonstrated the predictive performance of the PK/PD models.
Kowalski
K G
KG
Global Pharmacometrics, Pfizer Inc., Michigan, USA. ken.kowalski@pfizer.com
Olson
S
S
Remmers
A E
AE
Hutmacher
M M
MM
D000208:Acute Disease; D001578:Benzopyrans / Q000008:administration & dosage*; D002908:Chronic Disease; D003198:Computer Simulation / Q000639:trends; D018849:Controlled Clinical Trials as Topic / Q000379:methods* / Q000639:trends; D051546:Cyclooxygenase 2 / Q000097:blood; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D010146:Pain / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology
D001578:Benzopyrans; D052246:Cyclooxygenase 2 Inhibitors; C529433:SC-75416; D051546:Cyclooxygenase 2