Department of Hospital Pharmacy, Erasmus MC University Medical Center Rotterdam, Doctor Molewaterplein 40, PO Box 2040, 3015 GD, Rotterdam, The Netherlands.
Department of Intensive Care Adults, Erasmus MC University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Clin Pharmacokinet. 2022 Jul;61(7):973-983. doi: 10.1007/s40262-022-01122-5. Epub 2022 Apr 10.
Many patients treated for COVID-19 related acute respiratory distress syndrome in the intensive care unit are sedated with the benzodiazepine midazolam. Midazolam undergoes extensive metabolism by CYP3A enzymes, which may be inhibited by hyperinflammation. Therefore, an exaggerated proinflammatory response, as often observed in COVID-19, may decrease midazolam clearance. To develop a population pharmacokinetic model for midazolam in adult intensive care unit patients infected with COVID-19 and to assess the effect of inflammation, reflected by IL-6, on the pharmacokinetics of midazolam.
Midazolam blood samples were collected once a week between March 31 and April 30 2020. Patients were excluded if they concomitantly received CYP3A4 inhibitors, CYP3A4 inducers and/or continuous renal replacement therapy. Midazolam and metabolites were analyzed with an ultra-performance liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was developed, using nonlinear mixed effects modelling. IL-6 and CRP, markers of inflammation, were analyzed as covariates.
The data were described by a one-compartment model for midazolam and the metabolites 1-OH-midazolam and 1-OH-midazolam-glucuronide. The population mean estimate for midazolam clearance was 6.7 L/h (4.8-8.5 L/h). Midazolam clearance was reduced by increased IL-6 and IL-6 explained more of the variability within our patients than CRP. The midazolam clearance was reduced by 24% (6.7-5.1 L/h) when IL-6 increases from population median 116 to 300 pg/mL.
Inflammation, reflected by high IL-6, reduces midazolam clearance in critically ill patients with COVID-19. This knowledge may help avoid oversedation, but further research is warranted.
许多在重症监护病房接受 COVID-19 相关急性呼吸窘迫综合征治疗的患者使用苯二氮䓬类药物咪达唑仑进行镇静。咪达唑仑通过 CYP3A 酶广泛代谢，而超炎症可能会抑制这些酶。因此，COVID-19 中经常观察到的过度炎症反应可能会降低咪达唑仑的清除率。本研究旨在建立 COVID-19 感染的重症监护病房成年患者咪达唑仑的群体药代动力学模型，并评估炎症标志物 IL-6 对咪达唑仑药代动力学的影响。
2020 年 3 月 31 日至 4 月 30 日期间，每周采集一次咪达唑仑血样。如果患者同时接受 CYP3A4 抑制剂、CYP3A4 诱导剂和/或连续肾脏替代治疗，则将其排除在外。使用超高效液相色谱-串联质谱法分析咪达唑仑及其代谢物。采用非线性混合效应模型建立群体药代动力学模型。分析炎症标志物 IL-6 和 CRP 作为协变量。
咪达唑仑及其代谢物 1-羟基咪达唑仑和 1-羟基咪达唑仑葡萄糖醛酸的药代动力学数据符合单室模型。咪达唑仑清除率的人群平均估计值为 6.7 L/h（4.8-8.5 L/h）。IL-6 增加时，咪达唑仑清除率降低，IL-6 比 CRP 更能解释我们患者内的变异性。当 IL-6 从人群中位数 116 pg/mL 增加到 300 pg/mL 时，咪达唑仑清除率降低 24%（6.7-5.1 L/h）。
反映高 IL-6 的炎症会降低 COVID-19 重症患者咪达唑仑的清除率。这一认识可能有助于避免过度镇静，但还需要进一步的研究。
