Selecting drug combinations based on total equivalent dose (dose intensity)

We describe a mathematical model for selecting cytotoxic drugs and dosages for a combination regimen based on the antitumor activities of the drugs given as single agents and their organ-specific maximum tolerated doses. The regimen defined maximizes an approximate measure of antitumor effect subject to constraints on combined toxicity. This approach does not assume that the underlying dose-response curve is steep; nor does it assume that maximally dose-intense regimens are clinically appropriate in all situations. Whether the identified regimen is superior to standard treatments should be determined by prospective, randomized clinical trials. Determining which drugs to combine and in what proportions to combine them offers combinatorially huge numbers of possibilities. The method described here offers one approach to identifying combinations worthy of evaluation in prospective trials.