Chemical formula: C₂₁H₁₉BrN₄O₂ Molecular mass: 439.313 g/mol PubChem compound: 9867812
Remimazolam is an ultra-short acting benzodiazepine sedative. The effects of remimazolam on the CNS are dependent on the dose administered intravenously and presence or absence of other medicinal products. Remimazolam binds to benzodiazepine sites of gamma amino butyric acid type A [GABAA] receptors with high affinity, while its carboxylic acid metabolite (CNS7054) has approximately 300 times lower affinity for these receptors. Remimazolam does not show clear selectivity between subtypes of the GABAA receptor.
The primary pharmacodynamic effect of remimazolam is sedation. Sedation is observed starting at single bolus doses of 0.05 to 0.075 mg/kg in healthy young adults, with an onset of 1 to 2 min following dosing. Induction of mild to moderate sedation is associated with plasma levels of around 0.2 µg/mL. Loss of consciousness is seen at doses of 0.1 mg/kg (elderly) or 0.2 mg/kg (healthy young adults) and associated with plasma concentrations of around 0.65 µg/mL. Depth, duration and recovery from sedation is dose-dependent. Time to fully alert was 10 min for 0.075 mg/kg of remimazolam.
Remimazolam can cause anterograde amnesia after administration, which prevents patients from remembering events occurring during the procedure. Brice questionnaire data from 743 remimazolamtreated patients, assessed 10 minutes after the patient became fully alert and one day after the procedure, show that 76% of patients had no recollection of the procedure.
Remimazolam is administered intravenously.
Remimazolam has a mean distribution half-life (t1/2α) of 0.5 to 2 min. Its volume of distribution (Vz) is 0.9 L/kg. Remimazolam and its main metabolite (CNS7054) show moderate (~90%) binding to plasma proteins, predominantly albumin.
Remimazolam is an ester drug that is rapidly converted into the pharmacologically inactive carboxylic acid metabolite (CNS7054) by CES-1, mainly located in the liver.
The main route of metabolism of remimazolam is via conversion to CNS7054, which is then to a small extent further metabolized by hydroxylation and glucuronidation. Conversion to CNS7054 is mediated by liver carboxylesterases (primarily type 1A), with no meaningful contribution by cytochrome P450 enzymes.
In vitro studies have shown no evidence that remimazolam or CNS7054 inhibit cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2B6 and CYP2C8. There is no induction of the main inducible P450 isoenzymes 1A2, 2B6, and 3A4 in man. In vitro studies showed no clinically relevant influence of CES inhibitors and substrates on the metabolism of remimazolam. Remimazolam was not a relevant substrate of a panel of human drug transporters (OATP1B1, OATP1B3, BCRP, and MDR1 (=P-glycoprotein)). The same is true of CNS7054, tested for MRP2-4. By contrast, CNS7054 was found to be a substrate of MDR1 and BCRP. No or no relevant inhibition of the human drug transporters, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, MATE2-K, BCRP, BSEP, or MDR1, was seen with remimazolam or CNS7054.
Remimazolam has a mean elimination half-life (t1/2β) of 7 to 11 minutes. Clearance is high (68±12 L/h) and not related to body weight. In healthy subjects at least 80% of the remimazolam dose is excreted in urine as CNS7054 within 24 hours. Only traces (<0.1%) of unchanged remimazolam are detected in urine.
Remimazolam dose versus remimazolam maximal plasma concentration (Cmax) and total exposure (AUC0-∞) suggested a dose-proportional relationship in human volunteers in the dose range 0.01-0.5 mg/kg.
There is no significant effect of age on the pharmacokinetics of remimazolam given for procedural sedation.
The pharmacokinetics of remimazolam were not altered in patients with mild to end stage renal disease not requiring dialysis (including patients with a GFR <15 mL/min).
Severe impairment of hepatic function resulted in a reduced clearance and, as a consequence, a prolonged recovery from sedation.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxicity.
The following adverse reaction was not observed in clinical studies, but was seen in animals infused with the dosing solution of concentrations similar to the one used in clinical practice:
Primary lesions due to a mechanical irritation of the vessel wall during the puncture procedure can be aggravated by concentrations of remimazolam above 1 to 2 mg/mL (infusion) or above 5 mg/mL during bolus administration.
Reproductive toxicity studies performed at the maximum tolerated dose level revealed no influence on male or female fertility and on reproductive function parameters. In embryotoxicity studies in rats and rabbits, even at the highest dose levels, which displayed maternal toxicity, only marginal embryotoxic effects were observed (reduced foetal weight and slightly increased incidences of early and total resorptions). Remimazolam and its main metabolite are excreted in breast milk of rats and rabbits. The inactive main metabolite CNS7054 was detected in the plasma of suckling rabbit kits, however it is not known if remimazolam is transferred via milk to suckling offspring.
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