7/21/2019 Epilepsia Volume 36 Issue 3 1995 [Doi 10.1111%2Fj.1528-1157.1995.Tb00993.x] Wolfgang Lscher; Dagmar Hn

1/7

Epilepsia,

36(3):255-261, 1995

Raven P ress,

Ltd.,

N e w

Yofk

International League Ag am t

Epilepsy

New Injectable Aq ueous C arbam azepine Solution Through

Com plexing with

2-Hydroxypropyl-~-Cyclodextrin:

Tolerabili ty and Pharm acokinetics After Intra ve no us

Injection in C om parison

to a

Glycofurol-Based Formulation

Wolfgang Loscher, Dagmar Honack, Angelika Richter, *Hans-Ulrich Schulz,

Michael Schurer, fRaija Dusing, and $Marcus

E.

Brewster

Department of Pharma cology, Toxicology and Pharma cy, School of Veterinary Medicine , Hannover;

LAFAA

Laboratory fo r Contract Research in Clinical Pharmacology and Biopharmaceutical Analytics G m bH , Bad

Schwartau; fDesit in Arzneimittel Gm bH Hambu rg, German y; and SPharmos, Alachu a, Florida, U .S .A .

Summary: The poor water solubility of the antiepileptic

drug (AED) carbama zepine (CBZ) is generally considered

an absolu te contraindication to pa renteral administration

in epileptic patients. However, the water solubility of

CBZ can be largely enhanced through formation of an

inclusion complex with an a morp hous cyclodextrin deriv-

ative,

2-hydroxypropyl-~-cyclodextrin

HPPCD) . W e

studied tolerability and pharmacokinetics of an aqueous

CBZ:HPPCD solution afte r intravenous (i.v.) administra-

tion in dogs. For comparison,

a

conve ntiona l glycofurol-

based solution of CBZ wa s used. We also administered a

commercial liquid formulation of CB Z orally p.0.).nfu-

sion of CBZ:HPPC D solutions or HPP CD placebo for-

mulations i.v. was well tolerated by t he animals. In con-

trast, infusion of CB Z:glycofurol solutions and glycofurol

placebo solutions induced ma rked behavioral and cardio-

vascular adverse effects. Pharmacokinetic studies indi-

cated that glycofurol inhibited CBZ metabolism by de-

creasing formation of the major CBZ metabolite CBZ-

10,ll- epo xide (CBZ-E). With infusion of CBZ:HPPCD 10

ml/min for 12-15 min , resulting in

a

CBZ dose of CBZ 5

mg/kg body weight, peak CBZ plasma levels of -3.6 pgl

ml were obtained. This relatively low peak concentration

is primarily due to the rapid elimination of CBZ in dogs

[half-life (t )