Carabersat

Translating QT interval prolongation from conscious dogs to humans

Aim: In spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. Methods: Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between -0.98 ms μM-1 and 6.1 ms μM-1 in dogs and -10 ms μM-1 and 90 ms μM-1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species. Results: For compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x; R2 = 0.989). These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs. Conclusions: Together with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans.

Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions

This review briefly summarizes the information on the molecular mechanisms of action, pharmacokinetic profiles and drug interactions of novel (third-generation) antiepileptic drugs, including brivaracetam, carabersat, carisbamate, DP-valproic acid, eslicarbazepine, fluorofelbamate, fosphenytoin, ganaxolone, lacosamide, losigamone, pregabalin, remacemide, retigabine, rufinamide, safinamide, seletracetam, soretolide, stiripentol, talampanel, and valrocemide. These novel antiepileptic drugs undergo intensive clinical investigations to assess their efficacy and usefulness in the treatment of patients with refractory epilepsy.

Novel anticonvulsant medications in development

Epilepsy is currently the most prevalent neurological disorder worldwide. Pharmacological therapy remains the cornerstone of epilepsy treatment, however, refractory epilepsy is still a significant clinical problem despite the release of the second generation of anticonvulsants. Anticonvulsant treatment failures may result from lack of efficacy and presence of significant side effects. One rationale for incomplete effectiveness of the currently available anticonvulsants is that they were identified using the same classical models and therefore work largely by the same actions. These mechanisms fail to consider variations in the pathophysiological process that results in epilepsy, nor have they been shown to prevent the process of developing epilepsy (epileptogenesis). The next generation of anticonvulsants has taken into account the shortcomings of existing agents and attempted to improve on the currently available treatments using rationale drug design. This group of investigational anticonvulsants may be broadly classified as possessing one or more of the following: 1) increased tolerability through improvement in drug chemical structure or better delivery to the site of action, 2) new mechanisms (or combinations of mechanisms) of action, 3) improved pharmacokinetic properties. This article will discuss the next generation of anticonvulsants (carabersat, CGX-1007, fluorofelbamate, harkoseride, losigamone, pregabalin, retigabine, safinamide, SPD-421, talampanel, valrocemide) and the possible populations in which they would be clinically useful.

Prophylactic migraine therapy: emerging treatment options

In this paper, new treatment options for migraine prevention are reviewed. An overview about migraine pathophysiology is provided and current indications for migraine prevention and new and upcoming preventive medications are discussed briefly. Data are presented on topiramate, levetiracetam, zonisamide, botulinim toxin, tizanidine, nefazodone, lisinopril, candesartan, carabersat, petasites, and coenzyme Q.

Future prospects for the drug treatment of epilepsy

Great progress has been made in the last 150 years in the pharmacological management of epilepsy, and, despite the increasing number of technological advances available, antiepileptic drugs (AEDs) remain the mainstay of treatment for the vast majority of patients with epilepsy. This review looks at possible avenues of development in the drug treatment of epilepsy. The strengths and weaknesses of those AEDs which are currently licensed are examined, and ways in which their use may be improved are discussed (e.g. rational combinations, use of new formulations). Potentially new targets that may allow the development of effective treatments are highlighted (neuroimmunological manipulation, decreasing inherent drug resistance mechanisms, and modification of adenosine neurotransmission), and a summary of the most promising AEDs currently in development is provided [e.g. carabersat, ganaxolone, harkoseride, MDL 27192, safinamide (NW 1015), pregabalin, retigabine, talampanel, valrocemide, losigamone and BIA 2093].