Original Paper

Comparative Single-Dose Pharmacokinetics of Clonazepam following Intravenous, Intramuscular and Oral Administration to Healthy Volunteers
C. Crevoisier^a,b, M.C. Delisle^c, I. Joseph^a, G. Foletti<sup>c

a</sup>Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel,
^bClinical Pharmacology Services, Dornach, and
^cInstitution of Lavigny, Neurological and Educational Center, Lavigny, Switzerland

Address of Corresponding Author

Eur Neurol 2003;49:173-177 (DOI: 10.1159/000069089)

  Key Words

• Clonazepam
• Pharmacokinetics
• Bioavailability
• Intravenous
• Intramuscular
• Oral

  Abstract

The objective was to assess the single-dose pharmacokinetics of clonazepam following i.m., p.o. and i.v. administration. In an open-label, three-way crossover study, 12 healthy volunteers were randomized to receive a single dose of 2 mg clonazepam either by the i.m., p.o. or i.v. route. Serial blood samples were collected up to 120 h after drug administration. Plasma concentrations of clonazepam were determined by electron-capture gas-liquid chromatography. The absorption rates of clonazepam after i.m. and p.o. administration of clonazepam were significantly different from each other, as reflected by the respective mean values of maximum plasma concentration (C_max 11.0 vs. 14.9 ng·ml^-1) and time to reach maximum concentration (t_max 3.1 vs. 1.7 h). Secondary plasma peaks of clonazepam were observed in 9 volunteers after i.m. injection (C_max 9.9 ng·ml^-1; t_max 10.4 h). A comparison of the area under the plasma concentration-time curves (AUC) shows that the i.m. route is equivalent to the oral route (AUC_0- 620 vs. 561 ng·h·ml^-1). Clonazepam was almost completely absorbed after i.m. and p.o. administration, as shown by the mean absolute bioavailability of 93 and 90%, respectively. No significant differences existed between the elimination half-lives (i.v. 38.0 h; i.m. 43.6 h; p.o. 39.0 h). The average clearance and volume of distribution (V_Z) were 55 ml·min^-1 and 180 liters, respectively. In conclusion, the observed differences in C_max and t_max after i.m. and p.o. administration were consistent with a slower absorption rate of clonazepam after i.m. injection. The systemic exposure to clonazepam was not affected by the route of extravascular administration. Statistical evaluation of these kinetic data showed differences in the absorption rate, so that clonazepam given by the i.m. route is not bioequivalent to the oral route. On the basis of the results of this study, we would recommend the same i.m. and p.o. dose in epileptic patients, but therapeutic response would be expected to be less predictable and to occur later in the case of i.m. administration.

Copyright © 2003 S. Karger AG, Basel

  Author Contacts

Dr. C. Crevoisier
Clinical Pharmacology Services
Spitalweg 17
CH-4143 Dornach (Switzerland)
Tel./Fax +41 61 701 3946, E-Mail ch.crevoisier@intergga.ch

  Article Information

Received: July 2, 2002
Accepted: November 20, 2002
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 2, Number of References : 18