Midazolam is a benzodiazepine frequently used for sedation in patients hospitalized in the intensive care unit (ICU) for coronavirus disease 2019 (COVID-19). This drug is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes. Several studies have suggested that inflammation, frequently observed in these patients, could modulate CYP3A activity. The objective of this work was to study the impact of inflammation on midazolam pharmacokinetics in patients with COVID-19. Forty-eight patients hospitalized in the ICU for COVID-19 and treated with midazolam administered by continuous infusion were included in this study. Midazolam and α-hydroxymidazolam concentrations were measured and patient data, including the use of CYP3A inhibitors, were collected. Total and unbound concentrations of midazolam and α-hydroxymidazolam were measured in plasma using a validated liquid-chromatography coupled with mass spectrometry method. Inflammatory condition was evaluated by C-reactive protein (CRP) level measurement. Both drug concentrations and CRP measurements were performed on 354 plasma samples. CRP elevation was significantly associated with the α-hydroxymidazolam/midazolam plasma ratio decrease, whether for the unbound fraction or for the total fraction. Conversely, inflammation was not associated with protein binding modifications. Logically, α-hydroxymidazolam/midazolam plasma ratio was significantly reduced when patients were treated with CYP3A inhibitors. In this study, we showed that inflammation probably reduces the metabolism of midazolam by CYP3A. These results suggest that molecules with narrow therapeutic margins and metabolized by CYP3A should be administrated with care in case of massive inflammatory situations.

中文翻译：

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炎症对严重 COVID-19 患者咪达唑仑代谢的影响

咪达唑仑是一种苯二氮卓类药物，常用于重症监护病房 (ICU) 因 2019 冠状病毒病 (COVID-19) 住院的患者镇静。该药物主要由细胞色素 P450 3A (CYP3A) 同工酶代谢。几项研究表明，在这些患者中经常观察到的炎症可以调节 CYP3A 活性。这项工作的目的是研究炎症对 COVID-19 患者咪达唑仑药代动力学的影响。本研究纳入了 48 名因 COVID-19 在 ICU 住院并接受咪达唑仑持续输注治疗的患者。测量了咪达唑仑和 α-羟基咪达唑仑的浓度，并收集了患者数据，包括使用 CYP3A 抑制剂。使用经过验证的液相色谱结合质谱法测量血浆中咪达唑仑和 α-羟基咪达唑仑的总浓度和游离浓度。通过 C 反应蛋白 (CRP) 水平测量评估炎症状况。对 354 个血浆样本进行了药物浓度和 CRP 测量。CRP 升高与 α-羟基咪达唑仑/咪达唑仑血浆比率降低显着相关，无论是未结合部分还是总部分。相反，炎症与蛋白质结合修饰无关。从逻辑上讲，当患者接受 CYP3A 抑制剂治疗时，α-羟基咪达唑仑/咪达唑仑血浆比率显着降低。在这项研究中，我们发现炎症可能会降低 CYP3A 对咪达唑仑的代谢。