Maximum Tolerable Dose ( MTD )

The “Maximum Tolerable Dose” (MTD), also known as the “Maximum Tolerated Dose” or the “Maximally Tolerated Dose”, is defined as the dose that produces an “acceptable” level of toxicity or that, if exceeded, would put animals or patients at “unacceptable” risk for toxicity. Besides determining animal toxicology, establishing the MTD is the main objective of Phase I clinical trials, mostly in cancer and HIV treatment in which relatively high doses of drugs are usually chosen to achieve the greatest possible beneficial antitumor effect. Definition of the MTD usually relies on the sample, as MTD is defined as the dose level at which more than two patients over six experienced dose‐limiting toxicity (DLT). More recently, the MTD has been defined as the dose that produces a certain frequency of DLT within the treated patient population. In this framework, the MTD is estimated from the data using Bayes or maximum likelihood inference. In all these designs, the MTD is established for one initial administration or treatment course of a cytotoxic experimental agent, ignoring efficacy. To address these issues, the maximum tolerated schedule and the most successful dose have been proposed to be used rather than a conventional MTD. Finally, the concept of MTD that uses toxicity as a surrogate endpoint for efficacy in cytotoxic Phase I trials has been also controversial. Interests in alternatives to MTD have gained recently when dealing with new cytostatic agents that may produce relatively minimal organ toxicity, compared with standard cytotoxics. New optimal doses should be defined in the near future.