Unravelling the effects of acute inflammation on pharmacokinetics: a model-based analysis focusing on renal excretion and CYP3A4-mediated metabolism
Feiyan Liu(1), Linda B.S. Aulin(2), Martijn Manson(1), Elke H.J. Krekels(1), J. G. Coen van Hasselt(1)
(1)Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands;(2)Department of Clinical Pharmacy & Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany
Objectives: Acute inflammation, caused by infections or sepsis, can impact pharmacokinetics (PK). Here, we used a model-based analysis to evaluate the effect of acute inflammation on drug clearance focusing on renal excretion and CYP3A4-mediated metabolism.
Methods: A physiologically-based model incorporating renal and hepatic drug clearance was implemented. Functions were derived correlating IL-6 levels with glomerular filtration rate (GFR) and in vitro CYP3A4 activity, which were incorporated in the modeling framework. We then simulated treatment scenarios for hypothetical drugs varying the IL-6 levels, the contribution of renal and hepatic drug clearance, and protein binding. The relative change in observed area under the curve (AUC) was computed for these scenarios.
Results: Inflammation showed opposite effects on drug exposure for drugs eliminated via liver and kidney, with the effect of inflammation being inversely proportional to the extraction ratio (ER). For renally cleared drugs, the relative decrease in AUC was close to 30% during severe inflammation. For CYP3A4-substrates, the relative increase in AUC could exceed 50% for low ER drugs. Finally, the impact of inflammation-induced changes in drug clearance are smaller for drugs with a larger unbound fraction.
Conclusions: This analysis demonstrates differences in the impact of inflammation on drug clearance for different drug types. The effects of inflammation status on PK may explain the inter-individual variability in PK in critically ill patients. The proposed model-based analysis may be used to further evaluate the effect of inflammation, i.e., incorporating the effect of inflammation on other drug metabolizing enzymes or physiological processes.