The non-GLP toleration/dose range finding study: design and methodology used in an early toxicology screening program

A major directive of Pharmaceutical Research and Development (R&D) is to efficiently advance potential new chemical entities (NCEs) from the Discovery therapeutic area into Global Preclinical Development (GPCD), where a safety profile can be established. To facilitate the transition a comprehensive toxicity evaluation is required. In order to support both the R&D Discovery teams and GPCD, investigative (non-GLP) tolerance/dose range finding studies are conducted. These studies are designed to provide a quality toxicological and toxicokinetic assessment of potential NCEs early in the drug development process. During tolerance evaluations, compounds are first assessed in a single dose escalation (SDE) phase where rodents (or canines) receive a single dose anticipated to achieve relevant multiples of the efficacious dose. Data from this phase evaluates NCE absorption, and assists in estimating the maximum tolerated dose for a single administration and establish doses for a repeat dose (RD) phase. Data from the RD phase are used to determine potential target tissues of toxicity and also select doses for future GLP Toxicology studies. Thus, a rapid assessment of the toxicological profile of the NCE can be made to establish initial safety facilitating conduct of subsequent regulatory Toxicological studies and potentially earlier entry into clinical trials.