Journal
REGULATORY TOXICOLOGY AND PHARMACOLOGY
Volume 37, Issue 1, Pages 66-72Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/S0273-2300(02)00028-4
Keywords
occupational exposure limits; safety factors; uncertainty factors; toxicokinetics; pharmaceuticals; variability
Categories
Ask authors/readers for more resources
An approach for deriving occupational exposure limits (OEL) for pharmaceutical compounds is the application of safety factors to the most appropriate pre-clinical toxicity endpoint or the lowest therapeutic dose (LTD) in humans. Use of this methodology can be limited when there are inadequate pre-clinical toxicity data or lack of a well-defined therapeutic dose, and does not include pharmacokinetic considerations. Although some methods have been developed that incorporate pharmacokinetics, these methods do not take into consideration variability in response. The purpose of this study was to investigate how application of compartmental pharmacokinetic modeling could be used to assist in the derivation of OELs based on target blood concentrations in humans. Quinidine was used as the sample compound for the development of this methodology though the intent was not to set an OEL for quinidine but rather to develop an alternative approach for the determination of OELs. The parameters for the model include body weight, breathing rate, and chemical-specific pharmacokinetic constants in humans, data typically available for pharmaceutical agents prior to large scale manufacturing. The model is used to simulate exposure concentrations that would result in levels below those that may result in any undesirable pharmacological effect, taking into account the variability in parameters through incorporation of Monte Carlo sampling. Application of this methodology may decrease some uncertainty that is inherent in default approaches by eliminating the use of safety factors and extrapolation from animals to humans. This methodology provides a biologically based approach by taking into consideration the pharmacokinetics in humans and reported therapeutic or toxic blood concentrations to guide in the selection of the internal dose-metric. (C) 2003 Elsevier Science (USA). All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available