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Chronopharmacokinetic study with prolonged infusion of midazolam
Abstract:
Physiological and temporal variation in the disposition of midazolam has been reported. In order to delineate the underlying mechanisms of these alterations, we infused in 5 healthy male volunteers for 26 hours midazolam at a rate of 0.025 mg/kg/h preceded by a bolus of 0.05 mg/kg. Thus, steady-state conditions were rapidly achieved. Plasma levels of midazolam were monitored on a 2-hourly basis during this period. In addition, the pharmacodynamic response to the new sedative/hypnotic benzodiazepine was characterised by a pencil tracking test, sedation index formed from visual analogue scales, and choice reaction time. In all subjects, small (4 to 16%) but clinically irrelevant fluctuations of steady-state plasma concentrations around 45 ng/ml were observed. During the night-time (11pm to 7am) plasma concentrations were slightly (p = 0.074) higher than during the daytime. Total plasma clearance varied from 563 to 823 ml/min. Plasma protein binding of midazolam was time independent. Since in only 1 of 5 subjects was a circadian rhythm observed, fluctuations in plasma midazolam concentrations under controlled and constant conditions are probably not of clinical significance.
Insights
This study investigated midazolam (a sedative) levels in healthy males over 26 hours. Small fluctuations were observed, with slightly higher levels at night, but these changes were not clinically significant.
Area of Science:
- Pharmacology
- Clinical Pharmacology
- Drug Metabolism
Background:
- Midazolam disposition can vary physiologically and temporally.
- Understanding these variations is crucial for optimizing sedative/hypnotic therapy.
- Previous reports suggest alterations in midazolam pharmacokinetics.
Purpose of the Study:
- To investigate the mechanisms behind physiological and temporal variations in midazolam disposition.
- To assess the impact of continuous midazolam infusion on plasma concentrations and pharmacodynamic responses.
- To determine the clinical significance of observed fluctuations in midazolam plasma levels.
Main Methods:
- Continuous 26-hour intravenous infusion of midazolam in 5 healthy male volunteers.
- Plasma midazolam concentrations monitored every 2 hours to achieve steady-state.
- Pharmacodynamic assessments included pencil tracking, sedation index, and choice reaction time.
- Analysis of total plasma clearance and plasma protein binding.
Main Results:
- Small, clinically irrelevant fluctuations (4-16%) in steady-state midazolam plasma concentrations (around 45 ng/ml) were observed.
- Plasma concentrations were slightly higher during nighttime (11 pm - 7 am) compared to daytime (p = 0.074).
- Total plasma clearance ranged from 563 to 823 ml/min, and plasma protein binding was time-independent.
Conclusions:
- Circadian rhythm was observed in only one subject, suggesting fluctuations are not clinically significant under controlled conditions.
- Continuous midazolam infusion rapidly achieves steady-state with minimal clinically relevant variations.
- The findings indicate that physiological and temporal variations in midazolam disposition are likely of minor clinical importance.