Toxicokinetics in drug development: an overview of toxicokinetic application in the development of PNU-101017, an anxiolytic drug candidate.
Curr Drug Metab
; 1(3): 243-54, 2000 Nov.
Article
en En
| MEDLINE
| ID: mdl-11465047
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.
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Banco de datos:
MEDLINE
Asunto principal:
Quinolinas
/
Ansiolíticos
/
Agonistas del GABA
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Curr Drug Metab
Asunto de la revista:
METABOLISMO
/
QUIMICA
Año:
2000
Tipo del documento:
Article
País de afiliación:
Estados Unidos