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

Reichard, John F.; Maier, Marc A.; Naumann, Bruce D.; Pecquet, Alison M.; Pfister, Thomas D.; Sandhu, Reena; Sargent, Edward V.; Streeter, Anthony J.; Weideman, Patricia A.

doi:10.1016/j.yrtph.2016.05.027

Cited by 41 publications

(10 citation statements)

References 42 publications

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“…As noted above, if prestudy kinetic predictions suggest the test article has bioaccumulative properties, the study duration could be extended to allow for achievement of steady-state levels. Alternatively, paired pharmacokinetic studies will be performed to allow kinetic-based adjustment of biological potency estimates 34 . Future studies will consider the use of an earlier time point to evaluate the temporal effects on biology and begin to associate early findings with later effects to build the necessary mechanistic bridges likely required for use of genomic dose-response results in a formal risk assessment setting.…”

Section: Addressing the Study Designmentioning

confidence: 99%

NTP Research Report on National Toxicology Program Approach to Genomic Dose-Response Modeling

2018

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Section: Addressing the Study Designmentioning

confidence: 99%

NTP Research Report on National Toxicology Program Approach to Genomic Dose-Response Modeling

2018

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“…Interspecies variation of xenobiotic metabolism is commonly, but inadequately known kinetic factor determining differences in effects of chemicals between species [Reichard 2016].…”

Section: Discussionmentioning

confidence: 99%

In vitro sulfonation of 7-hydroxycoumarin derivatives in liver cytosol of human and six animal species

et al. 2020

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1. Sulfonation is an important high affinity elimination pathway for phenolic compounds.2. In this study sulfonation of 7-hydroxycoumarin and 13 its derivatives were evaluated in liver cytosols of human and six animal species. 7-hydroxycoumarin and its derivatives are strongly fluorescent, and their sulfate conjugates are nonfluorescent at excitation 405 nm and emission 460 nm. A convenient fluorescence based kinetic assay of sulfonation was established.3. The sulfonation rate of most of the 7-hydroxycoumarin derivatives was low in liver cytosol of human and pig, whereas it was high with most compounds in dog and intermediate in rat, mouse, rabbit, and sheep. Sulfonation of the 7-hydroxycoumarin derivatives followed Michaelis-Menten kinetics with Km values of 0.1 -12 µM, Vmax of 0.005-1.7 µmol/(min * g protein) and intrinsic clearance (Vmax/Km) of 0.004-1.9 L/(min * g cytosolic protein). 4. Fluorescence based measurement of sulfonation of 7-hydroxycoumarin derivatives provides a sensitive and convenient high-throughput assay to determine sulfonation rate in different species and tissues and can be applied to evaluate sulfonation kinetics and inhibition.

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“…As toxicity is driven by high local concentrations at the site of contact rather than the systemic dose, it may be overly conservative to extrapolate between routes of administration. 16,19,20 ICH M7 addendum 5 monographs for dimethylcarbamyl chloride and hydrazine illustrate this approach, where careful review of carcinogenicity data reveals more potent carcinogenicity following inhalation administration. Site of contact nasal tumors are observed resulting in a lower TD 50 value compared to oral administration, therefore route-specific PDEs were derived.…”

Section: Determination Of Pdes/ais For Different Routes Of Exposurementioning

confidence: 99%

“…This may be necessary when toxicology studies for intravenous (iv) or subcutaneous administration are lacking and standards only exist for daily intake of substances in food, water (oral exposure), air and/or occupational exposure (inhalation/dermal exposure). Methods for adjusting for bioavailability have been well described previously, 19 and the ICH guideline for elemental impurity safety assessment in pharmaceuticals, ICH Q3D, 4 specifically addresses oral-to-parenteral extrapolation (Table 4). In the absence of relevant inhalation and parenteral data, including potential local tissue toxicity, one could apply an AF of 100 (assuming <1% bioavailability).…”

Section: Determination Of Pdes/ais For Different Routes Of Exposurementioning

confidence: 99%

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

et al. 2021

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A workshop entitled “Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis” was held at the 2018 Genetic Toxicology Association annual meeting. The objectives of the workshop were to provide an educational forum and use case studies and live multiple-choice polling to establish the degree of similarity/diversity in approach/opinion of the industry experts and other delegates present for some of the more challenging decision points that need to be considered when developing a compound-specific exposure limit (ie, acceptable intake or permissible or permitted daily exposure). Herein we summarize the relevant background and case study information for each decision point topic presented as well as highlight significant polling responses and discussion points. A common observation throughout was the requirement for expert judgment to be applied at each of the decision points presented which often results in different reasoning being applied by the risk assessor when deriving a compound-specific exposure limit. This supports the value of precompetitive cross-industry collaborations to develop compound-specific limits and harmonize the methodology applied, thus reducing the associated uncertainty inherent in the application of isolated expert judgment in this context. An overview of relevant precompetitive cross-industry collaborations working to achieve this goal is described.

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

Cited by 41 publications

References 42 publications

NTP Research Report on National Toxicology Program Approach to Genomic Dose-Response Modeling

NTP Research Report on National Toxicology Program Approach to Genomic Dose-Response Modeling

In vitro sulfonation of 7-hydroxycoumarin derivatives in liver cytosol of human and six animal species

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

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