Experimental Design for Testing Synergism in Drug Combination Studies

• Activity Number: 361
• Type: Contributed
• Date/Time: Wednesday, August 10, 2005 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Hongbin Fang*+ and Ming Tan
• Companies: University of Maryland and University of Maryland
• Keywords: dose-effect ; experimental design ; F-test ; nonparametric model ; synergism ; uniform design

Abstract

Drug combinations are an important strategy for cancer therapy. The key reason for a combination therapy is for its potential to achieve greater efficacy with less toxicity. Often, combinations of multiple drugs are tested in preclinical in vitro and/or in vivo models to provide a basis for potential clinical trials. A statistical approach is necessary because even the administration of precisely the same dose to virtually identical animals may result in different responses. Such data variation needs to be controlled in the experimental design and accounted for in the analysis to allow proper inference on the efficacy of combinations. The combination studies can be optimally designed, so that with moderate sample size, the joint action of two drugs can be estimated and the best combinations identified. In this paper, we first propose a novel nonparametric model according to single-agent response curves. Then, we propose an experimental design for joint action using uniform measure in this nonparametric model. Based on this design, we propose a robust F-test to detect departures from the additive action of two compounds and a method to determine sample sizes.