scholarly journals Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers

2020 ◽  
Vol 132 (4) ◽  
pp. 652-666 ◽  
Author(s):  
Andreas Eisenried ◽  
Jürgen Schüttler ◽  
Marco Lerch ◽  
Harald Ihmsen ◽  
Christian Jeleazcov
Keyword(s):  
Frequency Band ◽  
Sedation Score ◽  
Healthy Male ◽  
Emax Model ◽  
Healthy Male Volunteers ◽  
Male Volunteers ◽  
Prediction Probability ◽  
Continuous Eeg ◽  
Narcotrend Index ◽  
Sigmoid Emax Model

Abstract Background Remimazolam (CNS 7056) is a new ultra-short acting benzodiazepine for IV sedation. This study aimed to investigate the electroencephalogram (EEG) pharmacodynamics of remimazolam infusion. Methods Twenty healthy male volunteers received remimazolam as continuous IV infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Continuous EEG monitoring was performed by a neurophysiologic system with electrodes placed at F3, F4, C3, C4, O1, O2, Cz, and Fp1 (10/20 system) and using the Narcotrend Index. Sedation was assessed clinically by using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacodynamic models were developed for selected EEG variables and Narcotrend Index. Results EEG changes during remimazolam infusion were characterized by an initial increase in beta frequency band and a late increase in delta frequency band. The EEG beta ratio showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.79, and could be modeled successfully using a standard sigmoid Emax model. Narcotrend Index showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.74. The time course of Narcotrend Index was described by an extended sigmoid Emax model with two sigmoid terms and different plasma–effect equilibration times. Conclusions Beta ratio was identified as a suitable EEG variable for monitoring remimazolam sedation. Narcotrend Index appeared less suitable than the beta ratio for monitoring the sedative effect if remimazolam is administered alone. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers

2020 ◽  
Vol 132 (4) ◽  
pp. 636-651 ◽  
Author(s):  
Jürgen Schüttler ◽  
Andreas Eisenried ◽  
Marco Lerch ◽  
Jörg Fechner ◽  
Christian Jeleazcov ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Compartment Model ◽  
Sedation Score ◽  
Maximum Effect ◽  
Healthy Male ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Effect Site ◽  
Arterial Blood ◽  
Healthy Male Volunteers ◽  
Male Volunteers

Abstract Background Remimazolam (CNS 7056) is a new ultra–short-acting benzodiazepine for intravenous sedation and anesthesia. Its pharmacokinetics and pharmacodynamics have been reported for bolus administration. This study aimed to investigate the pharmacokinetics and pharmacodynamics of remimazolam after continuous infusion. Methods Twenty healthy male volunteers (20 to 38 yr, 64 to 99 kg) received remimazolam as continuous intravenous infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Pharmacokinetics of remimazolam and its metabolite were determined from arterial plasma concentrations. Sedation was assessed using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacokinetic-pharmacodynamic modeling was performed by population analysis. Hemodynamics and the electrocardiogram were also investigated. Results Pharmacokinetics was best described by a three-compartment model for remimazolam and a two-compartment model with transit compartment for the metabolite. Remimazolam showed a high clearance (1.15 ± 0.12 l/min, mean ± SD), a small steady-state volume of distribution (35.4 ± 4.2 l) and a short terminal half-life (70 ± 10 min). The simulated context-sensitive halftime after an infusion of 4 h was 6.8 ± 2.4 min. Loss of consciousness was observed 5 ± 1 min after start, and full alertness was regained 19 ± 7 min after stop of infusion. Pharmacodynamics of Modified Observer’s Assessment of Alertness and Sedation score was best described by a sigmoid probability model with effect site compartment. The half-maximum effect site concentration for a Modified Observer’s Assessment of Alertness and Sedation score less than or equal to 1 was 695 ± 239 ng/ml. The equilibration half-time between central and effect compartment was 2.7 ± 0.6 min. Mean arterial blood pressure decreased by 24 ± 6%, and heart rate increased by 28 ± 15%. Spontaneous breathing was maintained throughout the study. There was no significant prolongation of the QT interval of the electrocardiogram observed. Conclusions Remimazolam was characterized by a pharmacokinetic–pharmacodynamic profile with fast onset, fast recovery, and moderate hemodynamic side effects. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Glucocorticoid treatment is associated with dose-dependent insulin resistance in healthy male volunteers

2019 ◽  
Author(s):  
Riccardo Pofi ◽  
Ilaria Bonaventura ◽  
Nanthia Othonos ◽  
Thomas Marjot ◽  
Ahmed Moolla ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Healthy Male ◽  
Glucocorticoid Treatment ◽  
Healthy Male Volunteers ◽  
Male Volunteers ◽  
Dose Dependent

Liquid Chromatography-Tandem Mass Spectrometry Method for Ticagrelor and its Active Metabolite Determination in Human Plasma: Application to a Pharmacokinetic Study

2020 ◽  
Vol 16 (5) ◽  
pp. 602-608
Author(s):  
Niloufar Marsousi ◽  
Serge Rudaz ◽  
Jules A. Desmeules ◽  
Youssef Daali
Keyword(s):  
Clinical Trial ◽  
Formic Acid ◽  
Human Plasma ◽  
Active Metabolite ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Healthy Male ◽  
Coronary Syndrome ◽  
Healthy Male Volunteers ◽  
Male Volunteers

Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its Active Metabolite (AM) in human plasma over expected clinical concentrations. Methods: Samples were handled by Liquid-Liquid Extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively. Results: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 μL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM, respectively. Finally, the usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined. Conclusion: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 μL of plasma.

Tapentadol results in less deterioration of gastrointestinal function and symptoms than standard opioid therapy in healthy male volunteers

2021 ◽  
Author(s):  
Esben Bolvig Mark ◽  
Rasmus Bach Nedergaard ◽  
Tine Maria Hansen ◽  
Thomas Dahl Nissen ◽  
Jens Brøndum Frøkjær ◽  
...  
Keyword(s):  
Opioid Therapy ◽  
Gastrointestinal Function ◽  
Healthy Male ◽  
Healthy Male Volunteers ◽  
Male Volunteers
Sign in / Sign up

Export Citation Format

Share Document