Maximum Tolerated Dose (MTD) Studies in Drug Toxicology Assessments

In order to transition a new chemical entity (NCE) from the discovery arena into nonclinical development and potentially the clinic, a comprehensive nonclinical safety profile must be established. To support candidate selection for development, a maximum tolerated dose (MTD) study is conducted in a rodent and non-rodent animal species. The MTD study is designed to provide both a toxicology and toxicokinetic assessment of a NCE early in the development process. Doses tested in the MTD study are evaluated that provide the highest dose of a novel pharmacological treatment (the NCE) that produces an effect without unacceptable toxicity. Important information about the acute toxicological profile of an NCE are derived from the MTD study since it monitors parameters such as clinical observations, clinical pathology (i.e., clinical chemistry, hematology, and coagulation are assessed), body weight, and food consumption with increasing doses of the NCE. These parameters characterize the dose/exposure response profile of the NCE, possible target organ toxicity, and potential reversibility of findings. The study provides information for subsequent dose selection in repeated-dose toxicology studies.