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The elimination half-life and drug clearance of drugs following nonlinear kinetics can vary with dosage. The Michaelis-Menten parameters and drug concentration influence these factors. As the dose increases, the elimination half-life tends to lengthen, resulting in a reduction in clearance and a disproportionately larger area under the curve. The total clearance can be derived from the Michaelis-Menten equation for drugs following a one-compartment model.
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When it comes to infants and young children, they are typically administered smaller doses of medication in comparison to adults. This is primarily because their organ functions still need to fully develop, meaning their bodies are not as efficient at metabolizing or eliminating drugs. Additionally, their blood-brain barrier is more permeable than in adults. As a result, high concentrations of drugs can easily penetrate the central nervous system (CNS), potentially leading to neurological...
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Antiepileptic drugs, such as levetiracetam (Keppra) and brivaracetam (Briviact), have emerged as crucial tools in managing epilepsy. These medications exert their therapeutic effects by targeting the synaptic vesicle protein SV2A, a transmembrane glycoprotein primarily found in the brain.
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Proposal for reference values for the developmental effects of valproate based on human data using a benchmark dose

Isabelle Manière-Guerrero1, Erminio Bonizzoni2, Dina Battino3

  • 1The French Agency for Food, Environmental and Occupational Health and Safety (ANSES), Risk Assessment Department, 14 rue Pierre et Marie Curie, F-94701, Maisons-Alfort Cedex, France.

Regulatory Toxicology and Pharmacology : RTP
|February 24, 2023
PubMed
Summary

A toxicological reference value (TRV) was established for valproate following an accidental release. This value helps assess risks from airborne exposure, focusing on major congenital malformations in fetuses exposed in utero.

Keywords:
Benchmark doseChildrenCongenital malformationModelingNeurodevelopmentPregnant womenToxicological reference valueValproate

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Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants
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Area of Science:

  • Environmental Health
  • Toxicology
  • Reproductive Health

Background:

  • Accidental valproate release in France necessitated risk assessment for surrounding populations.
  • Lack of a pre-existing toxicological reference value (TRV) hindered proper risk evaluation.
  • Major congenital malformations (MCMs) linked to in utero valproate exposure are a known concern.

Purpose of the Study:

  • To determine a TRV for valproate via inhalation for environmental risk assessment.
  • To establish a safe exposure level for the general population following accidental release.
  • To address public health concerns regarding potential valproate exposure.

Main Methods:

  • Utilized data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) registry.
  • Modeled the dose-response relationship (DRR) between in utero valproate exposure and MCM prevalence.
  • Calculated a benchmark dose (BMD) representing a 5% increase in MCM risk, deriving a TRV with an uncertainty factor.

Main Results:

  • Identified MCMs as the critical effect for TRV derivation due to highest sensitivity.
  • Established a benchmark dose lower 95% confidence limit (BMD5%L95%) of 2.26 mg/kg/day.
  • Determined an oral TRV of 0.08 mg/kg/day and a respiratory TRV of 0.26 mg/m³.

Conclusions:

  • A TRV for valproate inhalation has been successfully established for risk assessment purposes.
  • The derived TRV provides a crucial tool for managing public health risks from airborne valproate.
  • This study highlights the importance of having established TRVs for chemicals in environmental health scenarios.