Physiologically based pharmacokinetic modeling of small molecules: How much progress have we made?

Area of Science:

• Pharmacokinetics and Drug Development
• Computational Biology
• Systems Pharmacology

Background:

• Physiologically based pharmacokinetic (PBPK) models are widely used in drug development and research.
• PBPK applications are expanding to predict drug interactions, disease effects, and disposition across the lifespan, including pregnancy and organ impairment.
• Model complexity has increased due to computational power and diverse platforms, with academic research advancing physiological representation and mathematical concepts.

Purpose of the Study:

• To review the current landscape of PBPK modeling applications.
• To highlight the gap in assessing PBPK model quality and defining acceptance criteria.
• To emphasize the need for scientific justification in PBPK model development and reporting.

Main Methods:

• Literature review of PBPK modeling applications and advancements.
• Analysis of trends in PBPK model complexity and physiological representation.
• Assessment of current practices in PBPK model acceptance criteria and justification.

Main Results:

• PBPK models have significantly advanced in capturing human physiology, incorporating complex mathematical models like segregated gut and series compartment liver models.
• Despite advancements, there is a notable lack of predefined criteria and scientific justification for PBPK model acceptance in many publications.
• Awareness of the need for model acceptance criteria is increasing, but implementation remains inconsistent.

Conclusions:

• Continued advancements in PBPK modeling require parallel progress in establishing robust model quality assessment and acceptance criteria.
• Artificial intelligence and machine learning offer potential for enhanced PBPK model evaluation and performance analysis.
• There is a critical need for improved training and standardization in PBPK modeling science within academia to ensure rigor and reliability.