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Therapeutic Index

Definition
Definition
Definition

The therapeutic index (TI) is a quantitative measure that compares the amount of a therapeutic agent that causes the desired effect to the amount that causes toxicity. It is typically expressed as the ratio of the toxic dose (TD50 or LD50) to the effective dose (ED50) in a given population. A higher TI indicates a greater margin of safety for a drug.

Importance in Computational Drug Discovery:

  • Guides the selection and optimization of drug candidates with favorable safety profiles.
  • Informs early-stage in silico screening by prioritizing compounds with predicted high efficacy and low toxicity.
  • Supports risk assessment and decision-making throughout the drug development pipeline.
  • Enables computational modeling of dose-response relationships, integrating pharmacodynamics, pharmacokinetics and toxicology data.
  • Facilitates virtual screening campaigns that incorporate both efficacy and toxicity endpoints.

Key Tools

  • Derek Nexus: Predicts toxicity endpoints to help estimate the safety margin of drug candidates.
  • ADMET Predictor: Provides in silico predictions of both efficacy and toxicity, supporting TI estimation.
  • pkCSM: Predicts pharmacokinetic and toxicity properties from molecular structure, aiding in TI assessment.
  • Simcyp Simulator: Simulates population-based pharmacokinetics and pharmacodynamics for TI modeling.
  • TOPKAT: Offers toxicity prediction models that can be integrated into TI calculations.

Literature

"The determination and interpretation of the therapeutic index in drug development"

  • Publication Date: 2012-09-01
  • DOI: 10.1038/nrd3801
  • Summary: This comprehensive review discusses methodologies for determining and interpreting the therapeutic index in drug development. It emphasizes the importance of integrating safety and efficacy data from both in vitro and in vivo studies to predict clinical outcomes effectively . This review discusses that in vitro and in vivo data are essential to consider, but should be interpreted with caution for determination of the TI in larger populations.

"Enhancing Drug Efficacy and Therapeutic Index through Targeted Drug Delivery"

  • Publication Date: 2017-03-30
  • DOI: 10.3389/fphar.2017.00155
  • Summary: This article explores strategies to improve the therapeutic index of drugs by employing targeted drug delivery systems. It highlights how such approaches can enhance drug efficacy while minimizing systemic toxicity .

"Narrow Therapeutic Index Drugs: FDA Experience, Views, and Future Directions"

  • Publication Date: 2024-01-01
  • DOI: 10.1002/cpt.3460
  • Summary: This paper provides insights into the FDA's perspective on narrow therapeutic index drugs, discussing regulatory considerations and the importance of precise dosing to ensure patient safety .

"Identification of the Key Target Profiles Underlying the Drugs of Narrow Therapeutic Index"

  • Publication Date: 2021-07-01
  • DOI: 10.1016/j.jpha.2021.06.002
  • Summary: This study identifies common target profiles among drugs with a narrow therapeutic index, offering insights into the molecular characteristics that contribute to their limited safety margins .

"Use of Drug Sensitisers to Improve Therapeutic Index in Cancer"

  • Publication Date: 2024-07-01
  • DOI: 10.3390/pharmaceutics16070928
  • Summary: This review discusses the application of drug sensitizers in oncology to enhance the therapeutic index of anticancer agents, focusing on strategies to increase tumor specificity and reduce adverse effects .