1 Plus 1 Equals 3: Searching for In Vivo Synergy

• Activity Number: 522
• Type: Contributed
• Date/Time: Wednesday, August 1, 2012 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Mandy Bergquist*+ and Jonathan Hommel and Andrea Acker and Mark Paulik
• Companies: GlaxoSmithKline and University of Texas Medical Branch and GlaxoSmithKline and GlaxoSmithKline
• Keywords: drug combination ; nonlinear ; response surface ; synergy ; dose response ; preclinical

Abstract

In some disease areas, there exist established pharmaceutical therapies with moderate efficacy - efficacy that is clearly better than a placebo, but far short of a cure. Toxicity concerns often prevent physicians from simply increasing compound doses to gain additional efficacy. Instead, research scientists may combine compounds, hoping that the compounds synergize to provide enhanced efficacy without increased toxicity. Developing such a combination requires finding compounds with synergy and then choosing both an optimal ratio of the compounds and an efficacious total dose of that ratio. Traditional methods for exploring drug combinations focus on detecting synergy in cellular or chemical assays under restrictive assumptions. In some disease areas, however, cellular models are poorly predictive of clinical outcomes, and preclinical scientists must rely on in vivo studies with accompanying sample size restrictions and highly variable responses. This poster summarizes the application of a nonlinear mixture amount model proposed by Minto et al. (2000) to characterize the dose-response relationship between two compounds in an in vivo drug combination study.