Details

Autor(en) / Beteiligte

• Haschke, Manuel
• Suter, Katja
• Hofmann, Sarah
• Witschi, Robert
• Fröhlich, Johannes
• Imanidis, Georgios
• Drewe, Jürgen
• Briellmann, Thomas A.
• Dussy, Franz E.
• Krähenbühl, Stephan
• Surber, Christian

Titel

Pharmacokinetics and pharmacodynamics of nasally delivered midazolam

Ist Teil von

• British journal of clinical pharmacology, 2010-06, Vol.69 (6), p.607-616

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

2010

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Nasal application of midazolam has been studied for a variety of indications. Due to the limited application volume, highly concentrated formulations are required to reach clinically relevant concentrations in adult patients. No data on the pharmacokinetics and pharmacodynamics of nasal midazolam formulations based on cyclodextrin and chitosan are available. WHAT THIS STUDY ADDS • Clinically effective midazolam concentrations can be reached within less than 10 min after nasal administration of highly concentrated formulations containing an equimolar amount of the solubilizer randomly methylated‐β‐cyclodextrin combined with the absorption enhancer chitosan. Immediate non‐invasive application of such formulations in emergency treatment of seizure patients by lay persons could offer clinical benefits in situations where intravenous access cannot be quickly established. AIMS To investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5–30 mg ml−1) complexed with cyclodextrin. METHODS An open‐label sequential trial was conducted in eight healthy subjects receiving single doses of 1 mg and 3 mg intranasally and 1 mg midazolam intravenously. Pharmacokinetic parameters were obtained by non‐compartmental and two‐compartmental models. Pharmacodynamic effects of midazolam were assessed using VAS and a reaction time test. RESULTS Mean bioavailability of midazolam after nasal administration ranged from 76 ± 12% to 92 ± 15%. With formulations delivering 1 mg midazolam, mean Cmax values between 28.1 ± 9.1 and 30.1 ± 6.6 ng ml−1 were reached after 9.4 ± 3.2–11.3 ± 4.4 min. With formulations delivering 3 mg midazolam, mean Cmax values were between 68.9 ± 19.8 and 80.6 ± 15.2 ng ml−1 after 7.2 ± 0.7–13.0 ± 4.3 min. Chitosan significantly increased Cmax and reduced tmax of midazolam in the high‐dose formulation. Mean ratios of dose‐adjusted AUC after intranasal and intravenous application for 1′‐hydroxymidazolam were between 0.97 ± 0.15 and 1.06 ± 0.24, excluding relevant gastrointestinal absorption of intranasal midazolam. The pharmacodynamic effects after the low‐dose nasal formulations were comparable with those after 1 mg intravenous midazolam. The maximum increase in reaction time by the chitosan‐containing formulation delivering 3 mg midazolam was greater compared with 1 mg midazolam i.v. (95 ± 78 ms and 19 ± 22 ms, mean difference 75.5 ms, 95% CI 15.5, 135.5, P < 0.01). Intranasal midazolam was well tolerated but caused reversible irritation of the nasal mucosa. CONCLUSIONS Effective midazolam serum concentrations were reached within less than 10 min after nasal application of a highly concentrated midazolam formulation containing an equimolar amount of the solubilizer RMβCD combined with the absorption enhancer chitosan.