The pharmacokinetics of vigabatrin in rat blood and cerebrospinal fluid

SummaryPurposeData on the blood pharmacokinetics of vigabatrin, an antiepileptic drug with a unique and novel mechanism of action, in the rat are sparse. Additionally, little is known of the kinetics of vigabatrin in the central cerebrospinal fluid (CSF) compartment. We therefore investigated the rate of penetration into and the inter-relationship between serum and CSF compartments following systemic administration of vigabatrin in the rat.MethodsSprague–Dawley rats were implanted with a jugular vein catheter and a cisterna magna catheter for blood and CSF sampling, respectively. Vigabatrin was administered by intraperitonial injection at three different doses (250, 500 and 1000mg/kg) and blood and CSF collected at timed intervals up to 8h. Vigabatrin concentrations in sera and CSF were determined by high performance liquid chromatography.ResultsVigabatrin concentrations in blood and CSF rose linearly and dose-dependently and the time to maximum concentration (Tmax) was 0.4 and 1.0h, respectively. Vigabatrin is not protein bound in serum and its elimination from serum (mean t1/2 values, 1.1–1.4h) is rapid and dose-independent. The efflux of vigabatrin from CSF was significantly slower than that seen for serum (mean t1/2 values, 2.2–3.3h).ConclusionsThe kinetics of vigabatrin are linear with rapid entry into CSF. However, although vigabatrin CSF kinetics parallel that seen in serum, CSF vigabatrin concentrations represent only 2% of concentrations seen in serum and do not reflect free drug concentrations in serum

Stir bar-sorptive extraction, solid phase extraction and liquid-liquid extraction for levetiracetam determination in human plasma: comparing recovery rates

Levetiracetam (LEV), an antiepileptic drug (AED) with favorable pharmacokinetic profile, is increasingly being used in clinical practice, although information on its metabolism and disposition are still being generated. Therefore a simple, robust and fast liquid-liquid extraction (LLE) followed by high-performance liquid chromatography method is described that could be used for both pharmacokinetic and therapeutic drug monitoring (TDM) purposes. Moreover, recovery rates of LEV in plasma were compared among LLE, stir bar-sorptive extraction (SBSE), and solid-phase extraction (SPE). Solvent extraction with dichloromethane yielded a plasma residue free from usual interferences such as commonly co-prescribed AEDs, and recoveries around 90% (LLE), 60% (SPE) and 10% (SBSE). Separation was obtained using reverse phase Select B column with ultraviolet detection (235 nm). Mobile phase consisted of methanol:sodium acetate buffer 0.125 M pH 4.4 (20:80, v/v). The method was linear over a range of 2.8-220.0 µg mL-1. The intra- and inter-assay precision and accuracy were studied at three concentrations; relative standard deviation was less than 10%. The limit of quantification was 2.8 µg mL-1. This robust method was successfully applied to analyze plasma samples from patients with epilepsy and therefore might be used for pharmacokinetic and TDM purposes.</p

Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina

Background: The antiepileptic drug (AED) vigabatrin (VGB) causes concentric visual field constriction. Anecdotal reports involving tiagabine (TGB) have implied that this may be a class effect of all AEDs with γ-aminobutyric acid (GABA)–related actions. We investigated the pharmacokinetic and pharmacodynamic profiles of VGB and TGB in rat brain and eye. Methods: Adult male rats (n = 8) were administered 0.9% saline (control), VGB (500 or 1,000 mg/kg), or TGB (5, 10, or 20 mg/kg). At 1 (TGB) and 4 hours (VGB) postdosing, the animals were killed, a blood sample was obtained, their brains were dissected into five anatomic regions, and the retina and vitreous humor were isolated from each eye. Samples were analyzed for GABA concentrations and the activity of the enzyme GABA-transaminase (GABA-T). Plasma and tissue drug concentrations were also determined. Results: VGB treatment produced a decrease in the activity of GABA-T and a rise in GABA concentrations in all tissues investigated. This effect was most pronounced in the retina. VGB concentrations were as much as fivefold higher in the retina than in the brain. TGB was without effect on GABA concentrations and activity of GABA-T. TGB concentrations were notably lower in the retina than in the brain. Conclusions: Accumulation of VGB in the retina, with or without an increase in GABA, may be responsible for the visual field constriction reported clinically. In contrast, TGB had no effect on GABA concentrations and did not accumulate in the retina. These results suggest that TGB is unlikely to cause visual field defects in humans

A comparative pharmacokinetic study of intravenous and intramuscular midazolam in patients with epilepsy

The pharmacokinetics of midazolam, a water soluble 1,4-benzodiazepine, has been studied in 12 patients (11 male, 1 female; age range 19-57 years) with epilepsy. All patients were taking hepatic enzyme inducing antiepileptic drugs (AEDs) on a regular basis. Midazolam (5 mg) was administered intravenously and 1 week later midazolam was administered intramuscularly, the dose used being dependent on the sedative response to the intravenous dose (10 mg, n = 2; 7 mg, n = 8; 5 mg, n = 2). Serial blood samples were collected at timed intervals for 5-7 h. After intravenous administration initial distribution was rapid with a mean half-life (t 1/2 /α) of 0.06 ± 0.03 h followed by a terminal half-life (t 1/2 β or γ) of 1.5 ± 0.3 h. Volume of distribution was 0.62 ± 0.27 l/kg. After intramuscular administration midazolam was rapidly absorbed with peak serum concentrations achieved at 25 ± 23 min. Two patients showed delayed absorption. Mean terminal half-life was 2.8 ± 1.7 h. The absolute bioavailability of intramuscular midazolam was calculated in 11 patients as 87 ± 18%.Peer reviewe

Brand-to-generic levetiracetam switch in patients with epilepsy in a routine clinical setting

Purpose The therapeutic equivalence of generic and brand antiepileptic drugs, based on studies performed on healthy volunteers, has been questioned. We compare, in a routine clinical setting, brand versus generic levetiracetam (LEV) bioequivalence in patients with epilepsy and also the clinical efficacy and tolerability of the substitution. Methods A prospective, open-label, non-randomized, steady-state, multiple-dose, bioequivalence study was conducted in 12 patients with epilepsy (5 females), with a mean age of 38.4 ± 16.2 years. Patients treated with the brand LEV (Keppra; UCB Pharma) were closely followed for a four-week period and subsequently switched to a generic LEV (Pharmaten) and followed for another four-week period. Blood samples were collected at the end of each 4-week period, during a dose interval for each formulation, for LEV concentration measurements by liquid chromatography mass spectrometry. Steady-state area under the curve (AUC) and peak plasma concentration (Cmax) data were subjected to conventional average bioequivalence analysis. Secondary clinical outcomes, including seizure frequency and adverse events, were recorded. Results Patients had epilepsy for a mean period of 14.1 ± 10.6 years and the mean daily LEV dose was 2583.3 ± 763.7 mg. The mean AUC ± SD and Cmax ± SD was 288.4 ± 86.3 (mg/L) h and 37.8 ± 10.4 mg/L respectively for brand LEV and 319.2 ± 104.7 (mg/L) h and 41.6 ± 12.3 mg/L respectively for the generic LEV. Statistic analysis showed no statistical significant difference in bioequivalence. Also, no change in seizures frequency and/or adverse events was recorded. Conclusions In our clinical setting, generic LEV was determined to be bioequivalent to brand LEV. Furthermore, seizures frequency or/and adverse events were not affected upon switching from brand to generic LEV. © 2017 British Epilepsy Associatio

The anti epileptic vigabatrin induces in the EEG of rats behaviour-independent increase of delta - and decrease of beta power

Item does not contain fulltextVigabatrin and diazepam both are GABAergic drugs. Vigabatrin enhances the concentration of endogenous GABA by inhibiting GABA-transaminase, while diazepam enhances the efficacy of the endogenous GABA present. As may be expected, the clinical effects of the two drugs overlap: e.g. both have anti-epileptic effects and both decrease the level of vigilance. The similarity of the effects on the EEG is however less clear. During slow-wave sleep, in drug-free rats, the EEG consists of high-voltage delta waves. Despite the induction of sleep, diazepam enhances the power of the high frequency beta band. This phenomenon is called pharmacological dissociation. In contrast, vigabatrin has been shown to slow down the EEG; the power in the delta and theta bands increases while that of the beta band decreases. However in those studies behavioural changes were not taken into consideration. The aim of the present study was to investigate, in the rat, the effect of vigabatrin on behaviour and on behaviour-related EEG