Optimal Design For Combination Experiments Of Multiple Drugs

Combination therapies of multiple drugs is an important approach to increase the chance for therapeutic success by inhibiting multiple pathways/targets.Analytic methods for studying drug combinations have received increasing attention because major advances in biomedical research have made available large number of potential agents for testing.The preclinical experiment on multi-drug combinations plays a key role in(especially cancer)drug development because of the complex nature of the disease,the need to reduce development time and costs.Despite recent progresses in statistical methods for assessing drug interaction,there is an acute lack of meth-ods for designing experiments on multi-drug combinations.The number of combinations grows exponentially with the number of drugs and dose-levels and it quickly precludes laboratory test-ing.Utilizing experimental dose-response data of single drugs and a few combinations along with pathway/network information to obtain an estimate of the functional structure of the dose-response relationship in silico,we propose an optimal design that allows exploration of the dose-effect sur-face with the smallest possible sample size in this paper.The simulation studies show the proposed methods perform well.