New Injectable Aqueous Carbamazepine Solution Through Complexing with 2‐Hydroxypropyl‐β‐Cyclodextrin: Tolerability and Pharmacokinetics After Intravenous Injection in Comparison to a Glycofurol‐Based Formulation

Abstract

The poor water solubility of the antiepileptic drug (AED) carbamazepine (CBZ) is generally considered an absolute contraindication to parenteral administration in epileptic patients. However, the water solubility of CBZ can be largely enhanced through formation of an inclusion complex with an amorphous cyclodextrin derivative, 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). We studied tolerability and pharmacokinetics of an aqueous CBZ:HP beta CD solution after intravenous (i.v.) administration in dogs. For comparison, a conventional glycofurol-based solution of CBZ was used. We also administered a commercial liquid formulation of CBZ orally (p.o.). Infusion of CBZ:HP beta CD solutions or HP beta CD "placebo" formulations i.v. was well tolerated by the animals. In contrast, infusion of CBZ:glycofurol solutions and glycofurol placebo solutions induced marked behavioral and cardiovascular adverse effects. Pharmacokinetic studies indicated that glycofurol inhibited CBZ metabolism by decreasing formation of the major CBZ metabolite CBZ-10,11-epoxide (CBZ-E). With infusion of CBZ:HP beta CD 10 ml/min for 12-15 min, resulting in a CBZ dose of CBZ 5 mg/kg body weight, peak CBZ plasma levels of approximately 3.6 micrograms/ml were obtained. This relatively low peak concentration is primarily due to the rapid elimination of CBZ in dogs [half-life (t1/2) < 1 h]. Comparison of peak plasma levels determined after p.o. administration of CBZ to dogs with peak CBZ levels previously determined after p.o. administration in humans indicated that about four times higher doses are needed in dogs to attain the same peak plasma levels as in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic study of a carbamazepine nanoemulsion in beagle dogs

“…There were no significant differences between the area under the concentration-time curve (AUC 0-∞ ), drug concentration at zero time (Cp 0 ), half-life (t 1/2 ), elimination rate constant (ke), mean residence time (MRT) and clearance (Cl TOT ) ( Table 1). The average t (1/2) was in agreement with values reported by Löscher et al (1995) and Brewster et al (1997) (36-38 min) for the i.v. administration of CBZ/HP␤CD complex in dogs.…”

“…Two approaches have been extensively studied in order to achieve this objective: (1) CBZ complexation with hydroxypropyl-␤-cyclodextrin (HP␤CD) (Brewster et al, 1991(Brewster et al, , 1997Löscher et al, 1995), and more recently (2) CBZ incorporation into nanoemulsions (Becirevic-Lacan et al, 2002;Akkar and Müller, 2003;Madhusudhan et al, 2007).…”

Cyclodextrins

“…So, when one compares the PK and PD properties of a drug from a CD formulation to those of a control formulation, one must ask, what is the proper control, the CD formulation or the alternative? For example, in comparing the PK properties of carbamazepine from a HP-β-CD formulation to a formulation using glycofural as a cosolvent, it was found that glycofural caused a significant change in the PK properties of carbamazepine by inhibiting carbamazepine's metabolism (Löscher et al, 1995) and showed significant signs of toxicity and alteration in the pharmacologic actions of barbiturates (Yasaka et al, 1978). Surfactants such as Cremophor EL and Tween 80 can cause idiosyncratic histamine release, with patients having to be rescued through the use of antihistamines and steroids.…”

Intravenous and Oral Pharmacokinetic Evaluation of a 2-Hydroxypropyl-β-cyclodextrin-Based Formulation of Carbamazepine in the Dog: Comparison with Commercially Available Tablets and Suspensions

“…24 The total areas under the plasma concentration-time curves (AUC∞) were obtained from the regression program or calculated with the linear trapezoid rule. Other parameters, including the distribution or appearance half-life (t1/2R), terminal elimination half-life (t1/2 ), as well as the mean residence time (MRT) were obtained directly from the regression software.…”