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Hyperinflammation Reduces Midazolam Metabolism in Critically Ill Adults with COVID-19
Clinical Pharmacokinetics ( IF 4.5 ) Pub Date : 2022-04-10 , DOI: 10.1007/s40262-022-01122-5
Tim J L Smeets 1 , Abraham J Valkenburg 2 , Mathieu van der Jagt 2 , Birgit C P Koch 1 , Henrik Endeman 2 , Diederik A M P J Gommers 2 , Sebastian D T Sassen 1 , Nicole G M Hunfeld 1, 2
Affiliation  

Background and Objective

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.

Methods

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.

Results

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.

Conclusions

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.



中文翻译:

过度炎症可降低 COVID-19 危重成人的咪达唑仑代谢

背景与目的

许多在重症监护室接受 COVID-19 相关急性呼吸窘迫综合征治疗的患者使用苯二氮卓类咪达唑仑进行镇静。咪达唑仑经过 CYP3A 酶的广泛代谢,可能被过度炎症抑制。因此,在 COVID-19 中经常观察到的过度促炎反应可能会降低咪达唑仑的清除率。在感染 COVID-19 的成人重症监护病房患者中开发咪达唑仑的群体药代动力学模型,并评估由 IL-6 反映的炎症对咪达唑仑药代动力学的影响。

方法

在 2020 年 3 月 31 日至 4 月 30 日期间每周收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,则被排除在外。使用超高效液相色谱-串联质谱法分析咪达唑仑和代谢物。使用非线性混合效应建模开发了群体药代动力学模型。IL-6 和 CRP(炎症标志物)作为协变量进行分析。

结果

数据通过咪达唑仑及其代谢物 1-OH-咪达唑仑和 1-OH-咪达唑仑-葡糖苷酸的单室模型进行描述。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)。咪达唑仑清除率因 IL-6 增加而降低,IL-6 比 CRP 更能解释我们患者体内的变异性。当 IL-6 从人群中位数 116 增加到 300 pg/mL 时,咪达唑仑清除率降低了 24% (6.7–5.1 L/h)。

结论

由高 IL-6 反映的炎症会降低 COVID-19 重症患者的咪达唑仑清除率。这些知识可能有助于避免过度镇静,但需要进一步研究。

更新日期:2022-04-10
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