Pharmacokinetics of Enteral Lormetazepam in Mechanically Ventilated ICU Patients with COVID-19: An Adjunct Sedative Study

• Published in: Clinical pharmacokinetics 2024-12, Vol.63 (12), p.1769-1776
• Main Authors: le Noble, Jos L M L, Shudofsky, Kimberly N, Foudraine, Norbert, Punt, Nieko, Janssen, Paddy K J
• Format: Article
• Language: English
• Subjects: Adult; Aged; COVID-19; COVID-19 Drug Treatment; Critical Illness - therapy; Female; Humans; Hypnotics and Sedatives - administration & dosage; Hypnotics and Sedatives - pharmacokinetics; Intensive Care Units; Lorazepam - administration & dosage; Lorazepam - analogs & derivatives; Lorazepam - pharmacokinetics; Male; Middle Aged; Original; Respiration, Artificial; Respiratory Distress Syndrome - therapy; SARS-CoV-2
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-024-01455-3

During the coronavirus disease 2019 (COVID-19) pandemic, sedative prescriptions surged, leading to shortages of midazolam. This study investigates lormetazepam as an adjunct sedative alternative to midazolam for mechanically ventilated patients with COVID-19. We aimed to determine the clinical pharmacokinetics (PK) of enterally administered lormetazepam and provide dosing recommendations. Critically ill patients with acute respiratory distress syndrome (ARDS) or COVID-19 requiring mechanical ventilation were enrolled in April 2020. Lormetazepam 2 mg every 12 h was administered enterally. Blood samples were collected to quantify lormetazepam and its glucuronide. PK analysis was conducted using a one-compartment model with the Edsim++ KinPop plugin. The primary PK parameters (means ± coefficient of variation [CV] %) for absorption constant (K ), volume of distribution (V /F), and clearance (CL/F) were 6.4 h , 207 L/70 kg, and 14.5 L/h/kg , respectively. V /F and CL/F median values were 2.64 L/kg and 2.53 mL/kg/min, respectively, with a half-life of 10.7 h. Lormetazepam's median ratio to its glucuronide was 11.5. Trough-guided dosing suggested alternatives of 0.92 mg three times daily, 1.62 mg twice daily, or 5.36 mg once daily. This is the first study to report a validated PK model for enterally administered lormetazepam as a sedative adjunct in critically ill adults on mechanical ventilation for ARDS and COVID-19. The model was internally validated using a bootstrap procedure. Adequate lormetazepam concentrations were achieved at prescribed doses, with no significant alterations in clearance or half-life. This population model may aid in dose optimization and sedation management for future intensive care unit (ICU) patients.