Toxicokinetic and toxicodynamic considerations when deriving health-based exposure limits for pharmaceuticals

• Published in: Regulatory toxicology and pharmacology Vol. 79; pp. S67 - S78
• Main Authors: Reichard, John F., Maier, M. Andrew, Naumann, Bruce D., Pecquet, Alison M., Pfister, Thomas, Sandhu, Reena, Sargent, Edward V., Streeter, Anthony J., Weideman, Patricia A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.08.2016
• Subjects: Animals; Area Under Curve; Area under the curve (AUC); Bioaccumulation; Bioavailability; Chemical specific adjustment factor (CSAF); Cmax; Drug Industry - legislation & jurisprudence; Drug Industry - standards; Guidelines as Topic; Half-Life; Health Policy; Human health risk assessment; Humans; Metabolic Clearance Rate; Models, Biological; No-Observed-Adverse-Effect Level; Occupational Exposure - adverse effects; Occupational Exposure - legislation & jurisprudence; Occupational Exposure - prevention & control; Occupational Exposure - standards; Occupational Health - legislation & jurisprudence; Occupational Health - standards; Pharmaceutical Preparations - classification; Pharmaceutical Preparations - standards; Pharmacodynamic; Pharmacokinetic; Policy Making; Risk Assessment; Species Specificity; Toxicity Tests; Toxicodynamic; Toxicokinetic; Toxicokinetics; Toxicodynamic; Cmax; Area under the curve (AUC); Bioaccumulation; Human health risk assessment; Toxicokinetic; Chemical specific adjustment factor (CSAF); Pharmacodynamic; Bioavailability; Pharmacokinetic; C(max)
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2016.05.027

The purpose of this paper is to describe the use of toxicokinetic (TK) and toxicodynamic (TD) data in setting acceptable daily exposure (ADE) values and occupational exposure limits (OELs). Use of TK data can provide a more robust exposure limit based on a rigorous evaluation of systemic internal dose. Bioavailability data assist in extrapolating across different routes of exposure to be protective for route-based differences of exposure. Bioaccumulation data enable extrapolation to chronic exposures when the point of departure (PoD) is from a short-term critical study. Applied in the context of chemical-specific adjustment factors (CSAFs), TK data partially replace traditional default adjustment factors for interspecies extrapolation (extrapolation from studies conducted in animals to humans) and intraspecies variability (to account for human population variability). Default adjustments of 10-fold each for interspecies and intraspecies extrapolation are recommended in several guidelines, although some organization recommend other values. Such default factors may overestimate variability for many APIs, while not being sufficiently protective for variability with other APIs. For this reason, the use of chemical specific TK and TD data are preferred. Making full use of existing TK and TD data reduces underlying uncertainties, increases transparency, and ensures that resulting ADEs reflect the best available science. •A number of TK parameters can be used to replace default adjustment factors.•TK data can also be used to adjust the point-of-departure (PoD) for intermittent dosing and to account for steady state.•Selection of the best TK parameter requires knowledge of the predictors of target tissue concentrations and expert judgement.