Simultaneous Exposure–Response Modeling of ACR20, ACR50, and ACR70 Improvement Scores in Rheumatoid Arthritis Patients Treated With Certolizumab Pegol

The Markovian approach has been proposed to model American College of Rheumatology's (ACR) response (ACR20, ACR50, or ACR70) reported in rheumatoid arthritis clinical trials to account for the dependency of the scores over time. However, dichotomizing the composite ACR assessment discards much information. Here, we propose a new approach for modeling together the three thresholds: a continuous‐time Markov exposure–response model was developed, based on data from five placebo‐controlled certolizumab pegol clinical trials. This approach allows adequate prediction of individual ACR20/50/70 time‐response, even for non‐periodic observations. An exposure–response was established over a large range of licensed and unlicensed doses including phase II dose‐ranging data. Simulations from the model (50–400 mg every other week) illustrated the range and sustainability of response (ACR20: 56–68%, ACR50: 27–42%, ACR70: 11–22% at week 24) with maximum clinical effect achieved at the recommended maintenance dose of 200 mg every other week. CPT Pharmacometrics Syst. Pharmacol . (2014) 3, e143; doi: 10.1038/psp.2014.41 ; published online 29 October 2014