Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
Eur J Drug Metab Pharmacokinet. 2023 Nov;48(6):623-631. doi: 10.1007/s13318-023-00852-6. Epub 2023 Sep 15.
BACKGROUND AND OBJECTIVES: Acute inflammation caused by infections or sepsis can impact pharmacokinetics. We used a model-based analysis to evaluate the effect of acute inflammation as represented by interleukin-6 (IL-6) levels on drug clearance, focusing on renal glomerular filtration rate (GFR) and cytochrome P450 3A4 (CYP3A4)-mediated metabolism.
A physiologically based model incorporating renal and hepatic drug clearance was implemented. Functions correlating IL-6 levels with GFR and in vitro CYP3A4 activity were derived and incorporated into the modeling framework. We then simulated treatment scenarios for hypothetical drugs by varying the IL-6 levels, the contribution of renal and hepatic drug clearance, and protein binding. The relative change in observed area under the concentration-time curve (AUC) was computed for these scenarios.
Inflammation showed opposite effects on drug exposure for drugs eliminated via the 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 is smaller for drugs with a larger unbound fraction.
This analysis demonstrates differences in the impact of inflammation on drug clearance for different drug types. The effects of inflammation status on pharmacokinetics may explain the inter-individual variability in pharmacokinetics in critically ill patients. The proposed model-based analysis may be used to further evaluate the effect of inflammation, i.e., by incorporating the effect of inflammation on other drug-metabolizing enzymes or physiological processes.
感染或败血症引起的急性炎症会影响药代动力学。我们使用基于模型的分析来评估白细胞介素 6（IL-6）水平代表的急性炎症对药物清除率的影响，重点关注肾肾小球滤过率（GFR）和细胞色素 P450 3A4（CYP3A4）介导的代谢。
我们实施了一个包含肾和肝药物清除的基于生理学的模型。推导了与 IL-6 水平与 GFR 和体外 CYP3A4 活性相关的函数，并将其纳入建模框架。然后，我们通过改变 IL-6 水平、肾和肝药物清除的贡献以及蛋白结合来模拟假设药物的治疗情况。对于这些情况，计算了观察到的浓度-时间曲线下面积（AUC）的相对变化。
炎症对通过肝脏和肾脏消除的药物的药物暴露表现出相反的影响，炎症的影响与提取比（ER）成反比。对于经肾清除的药物，严重炎症期间 AUC 的相对下降接近 30%。对于 CYP3A4 底物，低 ER 药物的 AUC 相对增加可能超过 50%。最后，对于具有较大未结合分数的药物，炎症引起的药物清除变化的影响较小。
这项分析表明，不同类型的药物清除率受到炎症的影响不同。炎症状态对药代动力学的影响可能解释了危重病患者药代动力学的个体间变异性。所提出的基于模型的分析可用于进一步评估炎症的影响，即通过纳入炎症对其他药物代谢酶或生理过程的影响。
