Unraveling the Effects of Acute Inflammation on Pharmacokinetics: A Model-Based Analysis Focusing on Renal Glomerular Filtration Rate and Cytochrome P450 3A4-Mediated Metabolism

• DOI: 10.1007/s13318-023-00852-6
• Publication Date: 2023-09-15T19:08:17Z
• Authors: Feiyan Liu; Linda B. S. Aulin; Martijn L. Manson; Elke H. J. Krekels; J. G. Coen van Ha...
• Keywords: Clearance

Acute inflammation caused by infections or sepsis can impact pharmacokinetics. We used a model-based analysis to evaluate the effect of acute as represented interleukin-6 (IL-6) levels on drug clearance, focusing renal glomerular filtration rate (GFR) and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. A physiologically based model incorporating hepatic clearance was implemented. Functions correlating IL-6 with GFR in vitro CYP3A4 activity were derived incorporated into modeling framework. then simulated treatment scenarios for hypothetical drugs varying levels, contribution protein binding. The relative change observed area under concentration-time curve (AUC) computed these scenarios. Inflammation showed opposite effects exposure eliminated via liver kidney, being inversely proportional extraction ratio (ER). For renally cleared drugs, decrease AUC close 30% during severe inflammation. substrates, increase could exceed 50% low-ER drugs. Finally, inflammation-induced changes is smaller larger unbound fraction. This demonstrates differences different types. status pharmacokinetics may explain inter-individual variability critically ill patients. proposed be further inflammation, i.e., other drug-metabolizing enzymes physiological processes.