Practical aspects of assessing toxicokinetics and toxicodynamics

Area of Science:

• Toxicology
• Pharmacology
• Drug Discovery

Background:

• High-throughput screening (HTS) programs in toxicology require a deep understanding of toxicokinetics and toxicodynamics (TK/TD) for accurate dose-response assessment.
• TK/TD data, typically from toxicology studies, are vital for mechanistic application in new drug selection.
• Validating novel toxicological endpoints and implementing TK/TD modeling can improve the predictive power of these screening programs.

Purpose of the Study:

• To review optimal data collection strategies for TK/TD knowledge.
• To examine the four essential components of a TK/TD knowledge base: target-specific exposure, toxicodynamics markers (with emphasis on kidney), histomorphological correlates, and human adverse event data.
• To highlight the necessity for developing new TK/TD approaches to create rational future screening programs.

Main Methods:

• Literature review focusing on optimal data collection for TK/TD.
• Analysis of the four key components of the TK/TD knowledge base.
• Discussion on the integration of TK/TD principles into HTS program design.

Main Results:

• Identified optimal approaches for collecting TK/TD data.
• Detailed the four critical components required for a comprehensive TK/TD knowledge base.
• Emphasized the need for advancements in TK/TD methodologies.

Conclusions:

• A robust TK/TD knowledge base is fundamental for designing and validating innovative HTS toxicology programs.
• Integrating target-specific exposure, toxicodynamics markers, tissue correlates, and human adverse event data is essential.
• Future drug development requires the creation of new TK/TD approaches to enhance rational screening programs.