Modeling Exposure to Understand and Predict Kidney Injury

Area of Science:

• Nephrology
• Pharmacokinetics
• Toxicology

Background:

• Drug-induced kidney injury (DIKI) necessitates understanding drug exposure in the kidney.
• Kidney physiology uniquely influences drug accumulation and exclusion, impacting toxicity.
• Blood concentrations may not always reflect kidney exposure accurately.

Purpose of the Study:

• To review mechanisms driving drug accumulation/exclusion in the kidney.
• To examine the role of these mechanisms in DIKI.
• To provide an overview of kidney physiologically based pharmacokinetic (PBPK) models.

Main Methods:

• Literature review of physiological, biochemical, and physicochemical properties affecting kidney drug disposition.
• Analysis of in vivo examples of DIKI driven by pharmacokinetic mechanisms.
• Overview of existing kidney PBPK model structures, applications, and limitations.

Main Results:

• Kidney's unique properties can lead to drug accumulation or exclusion, influencing toxicity.
• Physiologically based pharmacokinetic models are valuable tools for understanding DIKI.
• PBPK models aid in predicting drug interactions and patient population variability.

Conclusions:

• Understanding kidney-specific pharmacokinetics is crucial for managing DIKI.
• Kidney PBPK models offer a framework for studying drug disposition and toxicity.
• Further development of PBPK models is needed to address gaps in toxicology.