Dose Selection for Combination Drug Products
Objectives: Patients can benefit from combination drugs which improve efficacy or reduce dose. Regulatory guidances require demonstration of safety and efficacy and the superiority of the combination to either of the two drugs alone at the same doses. A graphical procedure can aid us in interpreting the dose response model and help us to choose dose combinations that can meet the goals of both patients and regulators. The findings of the new procedure are compared to traditional methods of assessing the value of a drug combination.
Methods: The scope of this work covers fixed-dose combinations of two drugs, where both are effective alone, where effect is measured by one continuous end-point with no PK interaction. Given a suitable response surface function, the gain surface can be defined as the difference between the response at any dose combination and the maximum response for each drug alone at the same doses. A graphical procedure combining the response surface and the gain surface is illustrated using data from published studies (combinations of simvastatin/ezetimibe and atorvastatin/gemcabene) [1, 2] or simulated data. The findings of empirical synergy assessment (Loewe additivity and Bliss independence ) are compared to the results of the new graphical method.
Results: Response surface methods can provide a description of the 3-D surface and allow for interpolation and prediction of favorable dose combinations. Using the dose response surface and the gain surface together, we can find dose combinations that allow for improvements in efficacy or reduction in dose and for which there is a high expected gain. The findings of empirical synergy assessment, however, may be in conflict with the new graphical procedure.
Conclusions: Dose selection for combination drug products is best done with a good prior understanding of the dose-response patterns and mechanisms of action of the component drugs. Response surface methods and mechanistic modeling methods can be used to describe the dose-response surface. A graphical procedure which combines the response surface and the gain surface can aid in the choice of doses which show potential for improvement in efficacy or potential for dose reduction. Lack of empirical synergy does not imply lack of improvement in efficacy or lack of potential for dose reduction.
 Herman D et al. 2005 "Strategies to Improve Model-based Decision-making During Clinical Development" PAGE Meeting, Pampaloma, Spain
 Mandema JW, et al. 2005. "Model-Based Development of Gemcabene, a New Lipid-Altering Agent". The AAPS Journal. 7(3): E513-E522
 Greco WR, et al. 1995 "The Search For Synergy: A Critical Review From A Response Surface Perspective" Pharmacol. Rev. 47: 331-385.