title: The non-GLP toleration/dose range finding study: design and methodology used in an early toxicology screening program.
abstract: 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.
authors: Global Preclinical Toxicology/Pathology, Johnson & Johnson PR&D, Raritan, NJ 08869, USA.
authors: Judith A
authors: JA
authors: Herlich
authors: Peter
authors: P
authors: Taggart
authors: Jim
authors: J
authors: Proctor
authors: Paul
authors: P
authors: Stahle
authors: Rolland
authors: R
authors: Colis
authors: LeRoy
authors: L
authors: Hall
authors: Michael K
authors: MK
authors: Pugsley
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D010599:Pharmacokinetics; D012107:Research Design; D018675:Toxicity Tests / Q000379:methods*; D043922:Toxicogenetics