Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment

Abstract

Background: Remimazolam is a new benzodiazepine for procedural sedation and general anaesthesia. The aim of this study was to characterise its pharmacokinetic properties and safety in renally and hepatically impaired subjects. Methods: Two separate trials were conducted in patients with hepatic (n¼11) or renal impairment (n¼11) compared with matched healthy subjects (n¼9 and n¼12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design' trial, using a single bolus of remimazolam 0.1 mg kg À1 i.v., whereas the renal impairment trial was an open-label trial of a single bolus dose of remimazolam 1.5 mg i.v. Remimazolam plasma concentrations over time were analysed by population pharmacokinetic modelling. Results: Remimazolam pharmacokinetic properties were adequately described by a three-compartment, recirculatory model. Exposure in subjects with severe hepatic impairment was 38.1% higher (i.e. clearance was 38.1% lower) compared with healthy volunteers. This increase caused a slightly delayed recovery (8.0 min for healthy, 12.1 min for moderate, and 16.7 min for severe hepatic impairment). With renal impairment, plasma clearance was comparable with that measured in healthy subjects. Simulations of C max after a bolus dose of 10 mg showed no relevant impact of hepatic or renal impairment. The overall incidence of adverse events was low, and all adverse events were mild. Conclusions: As C max after a remimazolam bolus i.v. was not affected by hepatic or renal impairment, no dose adjustments are required. No unexpected adverse events related to remimazolam were seen in subjects with renal or hepatic impairment. Clinical trial registration: Hepatic impairment trial: ClinicalTrials.gov, NCT01790607 (https://clinicaltrials.gov/ct2/show/ NCT01790607). Renal impairment trial: EudraCT Number: 2014-004575-23.

Efficacy and Safety of Remimazolam Tosilate versus Propofol for General Anesthesia in Cirrhotic Patients Undergoing Endoscopic Variceal Ligation

“…22 A recent study showed that the pharmacokinetic properties of RT were not affected by hepatic impairment without dose adjustments. 23 Moreover, flumazenil is a specific antagonist of RT. 24 Our study showed that the mean times to RoC and extubation in group R were significantly shorter than that in group P. Compared with propofol, RT significantly shortened the PACU stay time.…”

The Efficacy and Safety of Remimazolam Tosilate versus Etomidate-Propofol in Elderly Outpatients Undergoing Colonoscopy: A Prospective, Randomized, Single-Blind, Non-Inferiority Trial

“…25 In addition, remimazolam did not differ between elderly and younger patients or between patients with normal renal function and end-stage renal failure. 16 However, its use requires caution in patients with severe hepatic impairment, 26 which is why we excluded patients with abnormal liver function. We also excluded patients with opioid or alcohol abuse because mortality has been shown to be higher for certain categories of patients who use opioids for pain reduction or abuse drugs, such as opioids or alcohol.…”

“…Compared with patients in the RT group, the EP group's onset time was significantly higher in (41 s vs 32 [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] s, p < 0.05; Table 3). However, there were no significant differences in the procedure time (p = 0.846) or cecal intubation time (p = 0.320) between the two groups (Table 3).…”

Remimazolam: pharmacological characteristics and clinical applications in anesthesiology

“…One important factor to consider is how the pharmacokinetic properties of remimazolam are altered in various populations, particularly in elderly patients and those with renal or hepatic impairment. The pharmacokinetic properties were not significantly different between the elderly (median age: 66.0 years) vs. young (median age: 21.0 years) patients [ 18 ], patients with normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 ml/min/1.73 m 2 ) vs. those with end-stage renal failure (eGFR < 15 ml/min/1.73 m 2 ), and patients with normal hepatic function vs. those with mild/moderate hepatic dysfunction (Child-Pugh class A and B) [ 19 ]. In contrast, the area under the concentration-time curve value from zero to infinity (AUC 0-inf ) was higher and clearance was lower in patients with severe hepatic impairment (Child-Pugh class C) than those in normal healthy volunteers (38.1%, both).…”

“…In contrast, the area under the concentration-time curve value from zero to infinity (AUC 0-inf ) was higher and clearance was lower in patients with severe hepatic impairment (Child-Pugh class C) than those in normal healthy volunteers (38.1%, both). Consequently, remimazolam exposure may be increased, and elimination may be prolonged in patients with severe hepatic impairment; therefore, careful dosage adjustment is recommended for these patients [ 19 ]. However, these pharmacokinetic analyses were performed using sparse data from small populations; hence, large-scale randomized controlled studies are needed to clarify the safety profile of remimazolam in the aforementioned populations.…”