Development of a pharmacokinetic and pharmacodynamic model for intranasal administration of midazolam in older adults: a single-site two-period crossover study

Clemens Barends*, Izaak den Daas, Mendy Driesens, Anita Visser, Anthony Absalom, Pieter Colin

*Corresponding author for this work

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BACKGROUND: Intranasal midazolam can produce procedural sedation in frail older patients with dementia who are unable to tolerate necessary medical or dental procedures during domiciliary medical care. Little is known about the pharmacokinetics and pharmacodynamics of intranasal midazolam in older (>65 yr old) people. The aim of this study was to understand the pharmacokinetic/pharmacodynamic properties of intranasal midazolam in older people with the primary goal of developing a pharmacokinetic/pharmacodynamic model to facilitate safer domiciliary sedation care.

METHODS: We recruited 12 volunteers: ASA physical status 1-2, aged 65-80 yr, and received midazolam 5 mg intravenously and 5 mg intranasally on two study days separated by a 6 day washout period. Concentrations of venous midazolam and 1'-OH-midazolam, Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score, bispectral index (BIS), arterial pressure, ECG, and respiratory parameters were measured for 10 h.

RESULTS: Time to peak effect of intranasal midazolam for BIS, MAP, and SpO 2 were 31.9 (6.2), 41.0 (7.6), and 23.1 (3.0) min, respectively. Intranasal bioavailability was lower compared with intravenous administration (F abs 95%; 95% confidence interval: 89-100%). A three-compartment model best described midazolam pharmacokinetics following intranasal administration. A separate effect compartment linked to the dose compartment best described an observed time-varying drug-effect difference between intranasal and intravenous midazolam, suggesting direct nose-to-brain transport.

CONCLUSIONS: Intranasal bioavailability was high and sedation onset was rapid, with maximum sedative effects after 32 min. We developed a pharmacokinetic/pharmacodynamic model for intranasal midazolam for older persons and an online tool to simulate changes in MOAA/S, BIS, MAP, and SpO 2 after single and additional intranasal boluses.


Original languageEnglish
Pages (from-to)284-293
Number of pages10
JournalBritish Journal of Anaesthesia
Issue number2
Early online date31-May-2023
Publication statusPublished - Aug-2023

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