Influence of Remifentanil on the Pharmacokinetics and Pharmacodynamics of Remimazolam in Healthy Volunteers.
Summary
In a 24-subject crossover trial, remifentanil altered remimazolam PK/PD, reducing CNS7054 clearance and synergistically deepening sedation across MOAAS and BIS endpoints. Modeling identified remimazolam targets of ~200–275 ng/mL with 0–0.5 ng/mL remifentanil to maximize moderate sedation (MOAAS 2–3) probabilities.
Key Findings
- Remifentanil decreased apparent clearance of remimazolam’s metabolite CNS7054 (half-max inhibition at 8.0 ng/mL).
- Pharmacodynamic interaction detected across MOAAS, BIS, TOL, and TOTS endpoints.
- Simulated optimal targets for moderate sedation: remimazolam 200–275 ng/mL with 0–0.5 ng/mL remifentanil (MOAAS 2–3 probability ~44–45%).
Clinical Implications
Use lower remimazolam targets when co-administering remifentanil and anticipate deeper sedation and increased tolerance to stimulation; adjust TCI setpoints and monitoring (MOAAS/BIS) accordingly.
Why It Matters
Provides quantitative PK/PD interaction data and actionable target concentrations for a widely adopted ultra–short-acting benzodiazepine–opioid combination, informing safer, precise titration.
Limitations
- Healthy volunteers; external validity to surgical patients limited.
- Exposure–response for TOL and TOTS not fully characterized by design constraints.
Future Directions
Validation in perioperative patients (including elderly and comorbid), effect on recovery profiles, respiratory safety, and integration into closed-loop sedation systems.
Study Information
- Study Type
- RCT
- Research Domain
- Treatment
- Evidence Level
- I - Randomized, controlled crossover pharmacology trial
- Study Design
- OTHER