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

Jos L M L le Noble; Kimberly N Shudofsky; Norbert Foudraine; Nieko Punt; Paddy K J Janssen

doi:10.1007/s40262-024-01455-3

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

Clin Pharmacokinet. 2024 Nov 15. doi: 10.1007/s40262-024-01455-3. Online ahead of print.

Authors

Jos L M L le Noble^{1

2

3}, Kimberly N Shudofsky⁴, Norbert Foudraine⁵, Nieko Punt^{6

7}, Paddy K J Janssen^{4

8}

Affiliations

¹ Department of Clinical Pharmacy, VieCuri Medical Center Venlo, 5900 BX, Venlo, The Netherlands. [email protected].
² Department of Pharmacology and Toxicology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. [email protected].
³ Department of Intensive Care, VieCuri Medical Center, Tegelseweg 210, 5912 BL, Venlo, the Netherlands. [email protected].
⁴ Department of Clinical Pharmacy, VieCuri Medical Center Venlo, 5900 BX, Venlo, The Netherlands.
⁵ Department of Intensive Care, VieCuri Medical Center, 5900 BX, Venlo, The Netherlands.
⁶ Medimatics, 6229 HR, Maastricht, The Netherlands.
⁷ Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁸ Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center, 6202 AZ, Maastricht, The Netherlands.

PMID: 39546269
DOI: 10.1007/s40262-024-01455-3

Abstract

Background and objective: 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.

Methods: 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.

Results: The primary PK parameters (means ± coefficient of variation [CV] %) for absorption constant (K_a), volume of distribution (V_d/F), and clearance (CL/F) were 6.4 h^-1, 207 L/70 kg, and 14.5 L/h/kg^0.75, respectively. V_d/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.

Conclusion: 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.