Potential strategy for assessing QT/QTc interval for drugs that produce rapid changes in heart rate: Electrocardiographic assessment of the effects of intravenous remimazolam on cardiac repolarization.

AIMS: Remimazolam is a new, ultra-short-acting benzodiazepine developed for intravenous (IV) use during procedural sedation and in general anaesthesia. Two trials were conducted to characterize its effects on cardiac repolarization. METHODS: A thorough QT/QTc (TQT) study assessed electrocardiography effects of therapeutic and supratherapeutic doses of remimazolam and midazolam. To investigate whether RR-QT hysteresis effects due to rapid heart rate changes might have confounded the QTc assessments in the TQT trial, a second trial used continuous IV remimazolam infusion to achieve stable heart rates during periods of stable remimazolam plasma concentration. RESULTS: During the TQT, both compounds produced a 10-20-beats/min increase in heart rate within 30 seconds, persisting for 5-10 minutes. Within 30 seconds, the upper bound of the 2-sided 90% confidence interval for the placebo-corrected change from baseline for QTcI (ΔΔQTcI) exceeded 10 ms for both doses of remimazolam (ΔΔQTcI 7.2 [3.2, 11.2] ms for the 10 mg dose and 10.4 [6.5, 14.3] ms for the 20 mg dose) as well as for the 7.5-mg dose of midazolam (8.2 [4.4, 12.1] ms). At 2 minutes after IV bolus, the upper bound of the 2-sided 90% confidence interval for ΔΔQTcI exceeded 10 ms only for the remimazolam 20-mg dose (6.3 [2.3, 10.2] ms). During the second study, during periods of stable heart rate, remimazolam had no clinically significant effect on QTc (peak ΔΔQTcI 3.4 [-1.1, 7.6] ms). CONCLUSION: Remimazolam does not prolong cardiac repolarization (QTc). The methods reported here may allow assessment of the QTc effects of other drugs given by IV bolus.

Pharmacokinetics and pharmacodynamics of intranasal remimazolam-a randomized controlled clinical trial.

PURPOSE: Remimazolam is a novel and ultra-short-acting sedative currently developed for intravenous use in procedural sedation, general anesthesia, and ICU sedation. However, intravenous administration is not always appropriate, depending on the patient or setting. This study evaluated intranasal administration as a potential alternative route. METHODS: The study used a randomized, double-blind, 9 period cross-over design to compare the pharmacokinetics, pharmacodynamics, and safety of single intranasal doses of 10, 20, and 40 mg remimazolam (as powder or solution) with intranasal placebo and 4 mg intravenous remimazolam. RESULTS: Intranasal remimazolam powder had a consistent absolute bioavailability of approximately 50%; Tmax was 10 min; AUC and Cmax were dose-proportional. The higher doses of intranasal solution, however, resulted in decreasing bioavailability and loss of dose-proportionality in AUC and Cmax despite complete drug absorption due to partial swallowing of dose and the resulting first-pass effect. Pharmacodynamics were generally consistent with PK. Peak effects (drowsiness, relaxation, any, memory, response time) were in similar ranges after intranasal (10 to 40 mg) as intravenous (4 mg) dosing and were partially, but not consistently, dose-related. Safety results were generally consistent with other benzodiazepines; however, intranasal remimazolam (but not placebo) caused nasal discomfort/pain, in some cases even severe. CONCLUSIONS: Intranasal administration of remimazolam was safe and caused sedative effects. However, the severe pain and discomfort caused by intranasal remimazolam prohibit its use by this route of administration, at least with the currently available intravenous formulation.

A miniature pig model of pharmacological tolerance to long-term sedation with the intravenous benzodiazepines; midazolam and remimazolam.

As a new and ultra fast-acting IV benzodiazepine, pharmacological tolerance may be anticipated during long-term treatment with remimazolam e.g. in intensive care. In this context, tolerance is particularly relevant for withdrawal syndrome. However, apart from primates, existing models of sedative tolerance are unsuitable for remimazolam due to its excessive metabolic clearance (i.e. in rodents) or paradoxical responses (in dogs). Pigs are a well-established model species, especially for in-vivo drug safety studies, and appear a well suited as model for evaluation of remimazolam. In a series of experiments from dose-range-finding bolus and infusion studies through to 28-day continuous level sedation, we established a viable model of intravenous benzodiazepine sedation in NIBS micropigs to compare tolerance development during 28 days sedation with either midazolam or remimazolam. Dose increases after 28 days were lower for remimazolam (0 to 3-fold) than for midazolam (2 to 4-fold) and recovery times were approximately 40% faster for remimazolam vs midazolam. Tolerance to remimazolam is therefore likely in long-term human sedation and may be less than that seen for midazolam.

Population Pharmacokinetics of Remimazolam in Procedural Sedation With Nonhomogeneously Mixed Arterial and Venous Concentrations.

Remimazolam is an ultra-short acting benzodiazepine under development for procedural sedation and general anesthesia. Population pharmacokinetic analysis (PopPK) was conducted for remimazolam with arterial and venous samples previously, but results were limited by arterial-venous concentration differences and inaccurate central volume of distribution (V1) estimates. A new model was developed to describe covariate effects after accounting for arterial-venous differences. Arterial and venous plasma concentration-time data from 11 clinical trials were pooled for PopPK. Data from two constant-rate infusion studies were used to account for venous-to-arterial (VtoA) ratio within residual error and to accurately estimate V1. V1 and VtoA ratio from the pilot model were applied to the full dataset, where the optimal fixed/random effects and covariates were assessed. VtoA ratio was described using a maximum effect (Emax ) model during infusion and as a constant postdose. V1 was estimated as 4.83 L for a 70 kg subject and interindividual variability (IIV) on V1 could only be estimated in studies with early concentrations. IIV on clearance was low (22.9%). Covariates included effects of sex on clearance (women 10% > men), and race on clearance and steady-state volume of distribution (African Americans 16% < other races). Arterial-venous concentration differences were best described using an Emax model during infusion with a constant ratio after infusion, resulting in low residual error (20.7%). There are no clinically relevant dose adjustments needed for any covariates based on pharmacokinetic differences.

A population pharmacodynamic Markov mixed-effects model for determining remimazolam-induced sedation when co-administered with fentanyl in procedural sedation.

The clinical effects of remimazolam (an investigational, ultra-short acting benzodiazepine being studied in procedural sedation) were measured using the Modified Observer's Assessment of Awareness/Sedation Scale (MOAA/S). The objective of this analysis was to develop a population pharmacokinetic/pharmacodynamic model to describe remimazolam-induced sedation with fentanyl over time in procedural sedation. MOAA/S from 10 clinical phase I-III trials were pooled for analysis, where data were collected after administration of placebo or remimazolam with or without concomitant fentanyl. A Markov model described transition states for 35,356 MOAA/S-time observations from 1071 subjects. Effect-compartment models of remimazolam and fentanyl linked plasma concentrations to the Markov model, and drug effects were described using a synergistic maximum effect (Emax ) model. Simulations were performed to identify the optimal remimazolam-fentanyl combination doses in procedural sedation. Fentanyl showed synergistic effects with remimazolam in sedation. Increasing age was related to longer recovery from sedation. Patients with body mass index greater than 25 kg/m2 had ~30% higher rates of distribution from plasma to the effect site (keo), indicating a slightly faster onset of sedation. Simulations showed that remimazolam 5 mg was more appropriate than 4 or 6 mg when administered with fentanyl 50 µg. The model and simulations support that a combination of remimazolam 5 mg with fentanyl 50 µg is an appropriate dosing regimen and the dose of remimazolam does not need to be changed in elderly patients, but some elderly patients may have a longer duration of sedation.

Randomized Crossover Trial to Compare Abuse Liability of Intravenous Remimazolam Versus Intravenous Midazolam and Placebo in Recreational Central Nervous System Depressant Users.

Remimazolam (RMZ) is a new and ultra-fast-acting, short-duration intravenous benzodiazepine, a drug class associated with abuse potential. This trial was designed to compare the abuse potential of remimazolam with placebo and midazolam (MDZ), a well-characterized member of the same pharmacological class in healthy, recreational drug users 18-55 years-of-age, who demonstrated good drug tolerance and were able to discriminate between midazolam and placebo. At equipotent intravenous doses selected to produce effects ranging from mild/moderate to relatively strong sedation without loss of consciousness (RMZ: 5, 10 mg versus MDZ: 2.5, 5 mg), peak scores (Emax or Emin , respectively) for drug liking, good/bad/any effects, and sedation (drowsiness and relaxation) were significantly greater than placebo for both active drugs and were broadly comparable between RMZ and MDZ. In contrast, areas under the effect-time curves (TA_AUE) were notably lower for RMZ versus MDZ, particularly for measures of good and any effects, reflecting the shorter duration of action and consistent with the more rapid observed plasma clearance for RMZ versus MDZ and the lack of an active RMZ metabolite. Scores for willingness to take drug again were also lower for RMZ versus MDZ, but not significantly so. We concluded that the abuse potential of RMZ is comparable to or lower than that of MDZ, a drug known to have a low potential for intravenous abuse.

Time-to-Event Modeling for Remimazolam for the Indication of Induction and Maintenance of General Anesthesia.

Remimazolam is an ultra-short-acting benzodiazepine being investigated for induction and maintenance of general anesthesia and for procedural sedation. This dose-response analysis of 4 phase 2-3 studies evaluated covariates that may impact the pharmacodynamic profile (based on theoretical pharmacokinetic principles) and require dose adjustments in subpopulations, particularly elderly, and if remimazolam has cumulative properties. Covariates affecting the time to loss of consciousness and time to extubation were evaluated using Cox proportional hazards models. Factors affecting steady-state infusion rate required to produce adequate sedation were evaluated using linear regression. Variability in time to loss of consciousness was explained by induction dose, age, body mass index, and time from initiation of opioids to initiation of remimazolam. The steady-state infusion rate producing adequate sedation was higher in European than Japanese subjects due to differences in study design. American Society of Anesthesiologists physical status class 3 subjects had a 28% lower maintenance infusion rate than class 1 subjects. Other statistically significant covariates (American Society of Anesthesiologists class 2, estimated glomerular filtration rate, and sex) resulted in small (≤14%), non-clinically relevant differences. Factors affecting time to extubation included the last infusion rate (ie, tapering), the bispectral index score at the end of infusion, and sex. The time to extubation after remimazolam did not increase with increased cumulative dose of remimazolam or duration of surgery. This evaluation of remimazolam's pharmacodynamic profile, in the absence of pharmacokinetic data, informed dosing recommendations and showed that remimazolam does not have cumulative properties in the general anesthesia setting.

Population pharmacokinetic/pharmacodynamic modeling for remimazolam in the induction and maintenance of general anesthesia in healthy subjects and in surgical subjects.

STUDY OBJECTIVE: To evaluate factors affecting variability in response to remimazolam in general anesthesia. DESIGN: Plasma concentration-time data from 11 Phase 1-3 clinical trials were pooled for the population pharmacokinetic (popPK) analysis and concentration-bispectral index (BIS) data were pooled from 8 trials for popPK-PD analysis. A 3-compartment model with allometric exponents on clearance and volume described remimazolam concentrations over time. An effect compartment model with an inhibitory sigmoid Emax model was fit to the concentration-BIS data. Simulations were performed to assess sedation in general anesthesia and post-surgical sedation in healthy and sensitive populations. SETTING: General anesthesia and post-surgical sedation. PATIENTS: 689 subjects included in popPK and 604 subjects included in popPK-PD. Most subjects (>85%) were ASA Class 1 or 2, with the remaining subjects being ASA Class 3. INTERVENTIONS: Serial plasma concentrations and BIS scores. MEASUREMENTS: Standard intra-operative monitoring. MAIN RESULTS: PopPK model included an effect of extracorporeal circulation, ASA class, and sex on PK and a time-dependent clearance (~30% lower at 24 h) that was not related to cumulative dose. Co-administered remifentanil had a synergistic decrease in BIS with remimazolam. Remimazolam IC50 increased with cumulative dose. Onset was faster in overweight subjects and slower in Asian subjects. If using a weight-based regimen, simulations showed that remimazolam 6 mg/kg/h until loss of consciousness followed by 1 mg/kg/h during general anesthesia and 0.25 mg/kg/h for post-surgical sedation for up to 24 h is optimal, regardless of ASA class or sensitivity of subjects. CONCLUSIONS: If using a weight-based regimen, results illustrated an appropriate regimen of remimazolam for general anesthesia and post-surgical sedation in general and sensitive populations, although lower doses can be considered in elderly patients with a significant disease burden or in ASA Class 3 patients. The time-dependent change in clearance is not clinically relevant for up to 24 h.

Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine.

Voltage-gated sodium channels play a critical role in excitability of nociceptors (pain-sensing neurons). Several different sodium channels are thought to be potential targets for pain therapeutics, including Na(v)1.7, which is highly expressed in nociceptors and plays crucial roles in human pain and hereditary painful neuropathies, Na(v)1.3, which is up-regulated in sensory neurons following chronic inflammation and nerve injury, and Na(v)1.8, which has been implicated in inflammatory and neuropathic pain mechanisms. We compared the effects of lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], a new pain therapeutic, with those of lidocaine and carbamazepine on recombinant Na(v)1.7 and Na(v)1.3 currents and neuronal tetrodotoxin-resistant (Na(v)1.8-type) sodium currents using whole-cell patch-clamp electrophysiology. Lacosamide is able to substantially reduce all three current types. However, in contrast to lidocaine and carbamazepine, 1 mM lacosamide did not alter steady-state fast inactivation. Inhibition by lacosamide exhibited substantially slower kinetics, consistent with the proposal that lacosamide interacts with slow-inactivated sodium channels. The estimated IC(50) values for inhibition by lacosamide of Na(v)1.7-, Na(v)1.3-, and Na(v)1.8-type channels following prolonged inactivation were 182, 415, and 16 microM, respectively. Na(v)1.7-, Na(v)1.3-, and Na(v)1.8-type channels in the resting state were 221-, 123-, and 257-fold less sensitive, respectively, to lacosamide than inactivated channels. Interestingly, the ratios of resting to inactivated IC(50)s for carbamazepine and lidocaine were much smaller (ranging from 3 to 16). This suggests that lacosamide should be more effective than carbamazepine and lidocaine at selectively blocking the electrical activity of neurons that are chronically depolarized compared with those at more normal resting potentials.

Lacosamide.

Lacosamide is a new chemical entity being investigated as an adjunctive treatment for epilepsy, as well as monotherapy for diabetic neuropathic pain. Lacosamide appears to have a dual mode of action: selective enhancement of sodium channel inactivation and modulation of collapsin response mediator protein-2. Rapidly and completely absorbed after oral administration, lacosamide has an elimination half-life of approximately 13 hours and a low potential for drug interactions. Additionally, lacosamide exhibits linear, dose-proportional pharmacokinetics with low intra- and interpatient variability. Randomized controlled trials of adjunctive lacosamide (200, 400, and 600 mg/day) have demonstrated statistically significant reduction in median seizure frequency compared with placebo. In addition, 50% responder rates for lacosamide (400 and 600 mg/day) were statistically superior to placebo. The most frequently reported adverse events (> or =10% of lacosamide-treated patients) included dizziness, headache, and nausea. A double-blind, double-dummy randomized trial of intravenous lacosamide (30- and 60-minute infusion) as replacement for oral lacosamide showed that the safety and tolerability profiles were comparable for intravenous and oral lacosamide. The efficacy and safety results from completed clinical trials, as well as the favorable pharmacokinetic profile, suggest that lacosamide may represent a significant advance in antiepileptic drug therapy.

Effects of the novel antiepileptic drug lacosamide on the development of amygdala kindling in rats.

PURPOSE: The current treatment of epilepsy focuses exclusively on the prophylaxis or suppression of seizures and thus provides merely a symptomatic treatment, without clear influence on the course of the disease. There is a need for new drugs that act at different molecular targets than currently available antiepileptic drugs (AEDs) and for new therapies designed to block the process of epileptogenesis. In recent years, different research lines have examined the epileptogenic process in order to understand the different stages in this process, and with the hope that early recognition and intervention could prevent the development or progression of epilepsy. In animals, acquired epilepsy is studied most commonly with the kindling model and status epilepticus models. In the present study, we used the kindling model to evaluate whether the novel AED lacosamide affects kindling-induced epileptogenesis. This drug does not seem to act by any of the mechanisms of currently available AEDs, but the exact molecular mechanisms of action of lacosamide have not yet been clarified. METHODS: Groups of 9-10 rats were treated with either vehicle or different doses of lacosamide (3, 10, or 30 mg/kg/day) over 22-23 days during amygdala kindling. RESULTS: Daily administration of lacosamide during kindling acquisition produced a dose-dependent effect on kindling development. While the drug was inactive at 3 mg/kg/day, significant retardation of kindling was observed at 10 mg/kg/day, by which the average number of stimulations to reach kindling criterion was increased by >90%. A significant inhibitory effect on kindling acquisition was also observed with 30 mg/kg/day, but this dose of lacosamide was associated with adverse effects. CONCLUSIONS: The present data demonstrate that lacosamide, in addition to exerting anticonvulsant activity, has the potential to retard kindling-induced epileptogenesis. Whether this indicates that lacosamide possesses antiepileptogenic or disease-modifying potential needs to be further evaluated, including studies in other models of acquired epilepsy.