Oxcarbazepine and its active metabolite, (S)‐licarbazepine, exacerbate seizures in a mouse model of genetic generalized epilepsy

Abstract

SUMMARYOxcarbazepine (OXC), widely used to treat focal epilepsy, is reported to exacerbate seizures in patients with generalized epilepsy. OXC is metabolized to monohydroxy derivatives in two enantiomeric forms: (R)-licarbazepine and (S)-licarbazepine. Eslicarbazepine acetate is a recently approved antiepileptic drug that is rapidly metabolized to (S)-licarbazepine. It is not known whether (S)-licarbazepine exacerbates seizures. Here, we test whether OXC or either of its enantiomers exacerbates the number of spike-and-wave discharges (SWDs) in mice harboring the human c-aminobutyric acid A receptor (GABA A )c2(R43Q) mutation. OXC (20 mg/kg), (S)-licarbazepine (20 mg/kg), and (R)-licarbazepine (20 mg/kg) all significantly increased the number of SWDs, while their duration was unaffected. The potential for (S)-licarbazepine to exacerbate SWDs suggests that eslicarbazepine acetate should be used with caution in generalized epilepsy. Furthermore, generalized seizure exacerbation for first-, second-, and third-generation carbamazepine-based compounds is likely to occur through a common mechanism. KEY WORDS: Epilepsy, Antiepileptic drugs, Spike-and-wave, Seizure aggravation.Carbamazepine (CBZ) has been used for decades and remains a first-line antiepileptic drug (AED) for focal seizures. Its use is, however, contraindicated in certain forms of generalized epilepsy because of the potential for seizure exacerbation.1 The basis of seizure exacerbation is not clear, with early suggestions that it was a consequence of the pharmacologically active metabolite, CBZ 10,11-epoxide. Oxcarbazepine (OXC), a second-generation structural variant of CBZ was introduced to avoid the formation of the 10,11-expoxide with the view of reducing side effects. However, retrospective clinical studies suggest that OXC is also associated with seizure aggravation, 3 a finding supported by animal models. 4 OXC is metabolized through a reduction process to active monohydroxy derivatives (MHDs), specifically a pair of enantiomers: (S)-licarbazepine and (R)-licarbazepine. OXC metabolism to MHDs is stereo-selective in humans, with a higher proportion metabolized to (S)-licarbazepine (ratio of plasma concentration area under the curve = 5.4).5 Eslicarbazepine acetate (ESL) is a third-generation AED in the CBZ class that was recently approved in Europe and the United States as adjunctive therapy in adults with partialonset seizures with or without secondary generalization. 6 In humans, ESL undergoes extensive first-pass hydrolysis to its major active metabolite (S)-licarbazepine (also known as eslicarbazepine), which represents about 95% of the active moiety.7 There is some suggestion from the genetic absence epilepsy rat from Strasbourg (GAERS) model of generalized epilepsy that although OXC causes seizure exacerbation, MHDs do not. 4 A concern with this earlier work is that rats convert ESL to OXC making it difficult to experimentally

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

“…This implies that genetic principles that occur in human populations can be recapitulated in mouse models, providing the tools to interrogate complex heritability. The GABRG2 (R43Q) mouse model also has an expected pharmacosensitivity profile responding to first-line anti-absence drugs, ethosuximide and sodium valproate (Tan et al, 2007;Kim et al, 2015). The GABRG2 (Q390X) knock-in mouse model recapitulates the more severe seizure phenotype seen in patients with truncation mutations (Warner et al, 2016).…”

Reconsidering the role of selective sodium channel blockers in genetic generalized epilepsy

“…19 However, the role of sodium channel blockers in GGE treatment is still unclear since their use has been strongly discouraged due to the well-documented risk of epilepsy aggravation, also observed in animal models of absence epilepsy, in which the systemic use of sodium channel blockers has been largely associated with absence seizure worsening and spike-wave discharge prolongation on EEG. [20][21][22][23] Given the considerable number of patients with drug-resistant GGE, it is important to better understand the role of these ASMs in this type of epilepsy to potentially expand the therapeutic armamentarium, especially in patients with uncontrolled GTCS.…”

One-step lipase-catalysed preparation of eslicarbazepine

“…Eslicarbazepine (S-licarbazepine) is the pharmacologically active form of the antiepileptic drugs carbamazepine (CBZ, Tegretol®), oxcarbazepine (OXC, Trileptal®), RS-licarbazepine 1 and the key chiral intermediate of eslicarbazepine acetate (Exelief®) and carbamazepine (CBZ) has been utilized as a rstline antiepileptic drug (AED) for focal seizures. However, the toxic 10,11-epoxide metabolite of CBZ (Fig.…”