Influence of Remifentanil on the Pharmacokinetics and Pharmacodynamics of Remimazolam in Healthy Volunteers

Anesthesiology, vol. 142, pp. 666–679

Abstract

BACKGROUND: Synergistic effects between opioids and remimazolam on Bispectral Index (BIS) and Modified Observer's Assessment of Alertness and Sedation (MOAAS) score were previously described. This study aimed to characterize the influence of remifentanil on the sedative properties of remimazolam as measured by MOAAS, BIS, and tolerance to laryngoscopy or tetanic stimulation (TOL or TOTS) and to determine target concentrations that maximize MOAAS 2 or 3. METHODS: A three-period, crossover, dose-ranging clinical trial was performed in 24 healthy volunteers. In all periods, remimazolam was administered using a step-up and step-down target controlled infusion protocol (50 to 2,000 ng/ml). Stable remifentanil target concentrations of 0.5 ng/ml and 0.1 to 4.0 ng/ml were maintained in periods 2 and 3, respectively. Remifentanil, remimazolam, and CNS7054 (metabolite) concentrations and MOAAS, BIS, TOL, and TOTS were collected in each step of the target controlled infusion protocol. Data were analyzed using nonlinear mixed-effects models, where P ≤ 0.01 was considered significant. RESULTS: Remifentanil reduced the apparent clearance of CNS7054 with a half-maximum inhibition at 8.0 ng/ml (95% CI, 5.5 to 13.4 ng/ml). A pharmacodynamic interaction was detected on all endpoints. Simulations indicate that the probability of observing a MOAAS 2 or 3 is highest at remimazolam target concentration of 275, 250, or 200 ng/ml combined with 0, 0.1, or 0.5 ng/ml remifentanil resulting in probabilities of 45%, 45%, and 44%, respectively. Additionally, simulations indicate that the highest probability of observing TOTS and TOL was 93.3% and 85.5%, respectively, at the highest studied target concentrations. CONCLUSIONS: A pharmacokinetic and pharmacodynamic drug-drug interaction between remimazolam and remifentanil was quantified in this clinical trial. Appropriate target concentrations for MOAAS and BIS could be estimated, but for TOL and TOTS, the trial design did not allow to fully characterize the exposure-response relationship.

Authors 7

1. Remco Vellinga

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

2. Jeroen V. Koomen

   University Medical Center Groningen · University of Groningen · Medicines Evaluation Board

   Affiliation as printed

   Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Pharmacology, Toxicology and Kinetics, Dutch Medicines Evaluation Board, Utrecht, The Netherlands

3. Douglas J. Eleveld

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

4. Thomas Stöhr Aachen Department of Research and Development

   Paion (Germany)

   Affiliation as printed

   Department of Research and Development, Paion Deutschland GmbH, Aachen, Germany

5. Marija Pesic Aachen Paion Deutschland GmbH

   Paion (Germany)

   Affiliation as printed

   Paion Deutschland GmbH, Aachen, Germany

6. Michel M. R. F. Struys

   University Medical Center Groningen · University of Groningen · Ghent University

   Affiliation as printed

   Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium

7. Pieter J. Colin

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands