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Impact of Inflammation on Midazolam Metabolism in Severe COVID-19 Patients.
Le Carpentier, Edouard Charles; Canet, Emmanuel; Masson, Damien; Martin, Maëlle; Deslandes, Guillaume; Gaultier, Aurélie; Dailly, Éric; Bellouard, Ronan; Gregoire, Matthieu.
  • Le Carpentier EC; Laboratoire de Pharmacologie Clinique, CHU Nantes, Nantes Université, Nantes, France.
  • Canet E; Médecine Intensive Réanimation, CHU Nantes, Nantes Université, Nantes, France.
  • Masson D; Laboratoire de Biochimie, CHU Nantes, Nantes Université, Nantes, France.
  • Martin M; Médecine Intensive Réanimation, CHU Nantes, Nantes Université, Nantes, France.
  • Deslandes G; Laboratoire de Pharmacologie Clinique, CHU Nantes, Nantes Université, Nantes, France.
  • Gaultier A; Plateforme de Méthodologie et Biostatistique, CHU Nantes, Nantes Université, Nantes, France.
  • Dailly É; Laboratoire de Pharmacologie Clinique, CHU Nantes, Nantes Université, Nantes, France.
  • Bellouard R; Cibles et Médicaments des Infections et de l'Immunité, IICiMed, CHU Nantes, Nantes Université, Nantes, France.
  • Gregoire M; Laboratoire de Pharmacologie Clinique, CHU Nantes, Nantes Université, Nantes, France.
Clin Pharmacol Ther ; 112(5): 1033-1039, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1913780
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Midazolam / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Journal: Clin Pharmacol Ther Year: 2022 Document Type: Article Affiliation country: Cpt.2698

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Midazolam / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Journal: Clin Pharmacol Ther Year: 2022 Document Type: Article Affiliation country: Cpt.2698