Compromise design for combination experiment of two drugs

Abstract

Preclinical experiment on two-drug combination is a stepping stone to multi-drug combination studies. Experimental designs have been proposed in the literature to test the presence of synergism between the combined drugs. However, a design that is efficient for synergy testing is not necessarily desirable for dose–response modeling and the latter is important for future development on drug interaction analysis. This work proposes an experimental design, called a compromise design to meet the dual requirements on synergy testing and dose–response modeling. The key idea of the design is to spread the design points uniformly on a pair of design regions where synergy testing and dose–response modeling are respectively carried out. Simulations and two illustrative examples are given to demonstrate the usefulness of the compromise design. In the illustrative examples, the good balance of the proposed design is visualized by 2-D projections of the design points. The simulation results indicate that the compromise design performs satisfactorily in terms of both testing power and model prediction accuracy.