Breanne Mefford, PharmD,
Pharmacist
University of Kentucky Healthcare
Lexington, Kentucky
Disclosure information not submitted.
Chris Donaldson, PharmD
Pharmacist
University of Kentucky, United States
Disclosure information not submitted.
Brittany Bissell, BCCCP, PharmD, PhD
Clinical Pharmacist
University of Kentucky
Lexington, Kentucky
Disclosure information not submitted.
Title: Pharmacokinetic Influence of Tocilizumab on Midazolam in Critically Ill Patients with COVID-19
Introduction: Since the onset of coronavirus disease 2019 (COVID-19), the utilization of benzodiazepines for routine sedation in the intensive care unit (ICU) has increased secondary to unique sedative needs, drug shortages, and other patient-specific factors such as deep sedation for paralysis. Confounding their use are COVID-19-based therapies, such as tocilizumab, with the potential for drug-drug interaction (DDI). Interleukin-6 is known to down-regulate the mRNA cytochrome P450 expression (CYP) isozymes while more selectively reducing the expression of CYP3A4. As tocilizumab decreases IL-6 levels, CYP3A4 expression will increase thereby accelerating the clearance for which midazolam (a major CYP3A4 substrate) is metabolized. We describe the need of high dose midazolam after the utilization of tocilizumab in COVID-19 patients requiring continuous infusion midazolam while mechanically ventilated.
Description: Five critically ill COVID-19 patients with acute respiratory distress syndrome required high dose midazolam ( >0.1 mg/kg/h) in order to maintain sedation goals after the utilization of tocilizumab. Patient age ranged from 31 to 60 years old. Tocilizumab was most frequently administered once at a dose of 800 mg with the exception of two patients, one received 800 mg twice and one received 720 mg twice. Midazolam requirements ranged from 0.15-0.68 mg/kg/hr for a total duration of 3.1 to 15 days. Two patients died while three patients were transferred to rehabilitation facilities. No patient in our case series had liver dysfunction, and no CYP3A4 inducers were administered with the exception of dexamethasone (a weak inducer) per current guideline recommendations. Concentrations were not clinically evaluated as the relationship between midazolam concentration and the pharmacologic impact has not been well characterized.
Discussion: The utilization of tocilizumab is expected to increase as guideline recommendations include the use of tocilizumab in combination with dexamethasone in patients who are exhibiting rapid respiratory decompensation. Furthermore, given the long half-life of tocilizumab the impact on CYP3A4 metabolism may continue to persist. Clinicians need to be cognizant of the potential DDI surrounding tocilizumab and its impact on CYP3A4 metabolism as CYP3A4 is a major pathway for hepatic metabolism.