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Pharmacokinetics and pharmacodynamics of nasally delivered midazolam

Haschke, Manuel and Suter, Katja and Hofmann, Sarah and Witschi, Robert and Fröhlich, Johannes and Imanidis, Georgios and Drewe, Jürgen and Briellmann, Thomas A. and Dussy, Franz E. and Krähenbühl, Stephan and Surber, Christian. (2010) Pharmacokinetics and pharmacodynamics of nasally delivered midazolam. British journal of clinical pharmacology, Vol. 69, H. 6. pp. 607-616.

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Official URL: http://edoc.unibas.ch/dok/A5841932

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Abstract

To investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5-30 mg ml(-1)) complexed with cyclodextrin.; 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.; Mean bioavailability of midazolam after nasal administration ranged from 76 +/- 12% to 92 +/- 15%. With formulations delivering 1 mg midazolam, mean C(max) 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 C(max) 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 C(max) and reduced t(max) 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.; 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 RMbetaCD combined with the absorption enhancer chitosan.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Clinical Pharmacology (Drewe)
03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)
UniBasel Contributors:Krähenbühl, Stephan and Drewe, Jürgen
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Blackwell
ISSN:0306-5251
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:07 Dec 2012 13:03
Deposited On:07 Dec 2012 13:02

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