title: Toxicokinetics in drug development: an overview of toxicokinetic application in the development of PNU-101017, an anxiolytic drug candidate.
abstract: The importance of toxicokinetics in the drug development has been identified in the last decade. The main objectives of toxicokinetics in general are to define the drug bioavailability, dose proportionality, gender differences, and species differences in pharmacokinetics and metabolism, from which the target organ toxicity can be predicted and the safety doses in the first human clinical trial can be established. Toxicokinetic studies may also serve as a tool for the toxicologic pathologist in understanding models used for predicting and assessing drug-related toxic response. Toxicokinetics/toxicodynamics are critical to investigating the toxicological mechanism and understanding the comparative toxicity between animals and humans. This report presents an overview of the application of toxicokinetics and its impact in the drug development of PNU-101017, a drug candidate for the treatment of anxioety. Serial specifically designed toxicokinetic studies identified a steep dose-response relationship between the clinical signs and PNU-101017 serum or CSF concentrations, characterized the centrally mediated respiratory depression as the toxicity leading to the lethality, and demonstrated marked species differences in the sensitivity to the toxic effects. These findings lead to a termination of PNU-101017 development due to the safety concern in humans.
authors.affiliation: Drug Metabolism Research, Pharmacia Corporation, Kalamazoo, MI 49001, USA. wei-zhu.zhong@am.pnu.com
authors.forename: W Z
authors.initials: WZ
authors.lastname: Zhong
authors.forename: M G
authors.initials: MG
authors.lastname: Williams
authors.forename: D G
authors.initials: DG
authors.lastname: Branstetter
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D018755:GABA Agonists / Q000493:pharmacokinetics* / Q000633:toxicity*; D011485:Protein Binding; D011804:Quinolines / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution
chemical_list: C104547:7-chloro-5((cis-3,5-dimethylpiperazine)carbonyl)imidazo(1,5a)quinoline-3-carboxylate; D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D011804:Quinolines