Pharmacokinetic Drug-Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients.

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.

OBJECTIVE: Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. METHODS: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a+/- mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a+/- mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together. RESULTS: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation. SIGNIFICANCE: Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.

Perampanel chronic treatment does not induce tolerance and decreases tolerance to clobazam in genetically epilepsy prone rats.

Tolerance to some therapeutic effects of antiepileptic drugs may account for the development of pharmacoresistance in patients with epilepsy. In the present study, following oral acute pretreatment with the new antiepileptic drug perampanel (0.1, 0.3, 1 or 3 mg/kg), we observed that the drug significantly and dose-dependently attenuated the seizure phases (clonus and tonus) of audiogenic seizures in genetically epilepsy prone rats (GEPR-9 s), a genetic model of reflex generalized epilepsy. In addition, the GEPR-9 s were administered orally with perampanel (1 or 3 mg/kg) once daily for 10 weeks in order to study the possible development of tolerance, and when animals were subjected to auditory stimulation we observed that the ED50 values against clonus or tonus were not significantly different from those observed after single administration. Furthermore, the duration of anticonvulsant effects observed between 60 min and 9 h following oral administration of perampanel (1 mg/kg) were similar in acute and after chronic treatment. In another group of experiments, clobazam (0.75, 1.5, 3, 6, 9, 12 and 15 mg/kg) after acute administration was able to dose-dependently reduce the severity of the audiogenic seizures in GEPR-9 s. When clobazam (6 or 12 mg/kg) was administered alone for 10 consecutive weeks a clear development of tolerance to its anticonvulsant effects within approximately seven weeks was observed. In addition, we observed that when clobazam (6 mg/kg) was co-administered with perampanel (1 mg/kg), the latter drug was able to attenuate the development of tolerance to the antiseizure activity of clobazam. The present data indicate that both perampanel and clobazam are effective against audiogenic seizures, however, clobazam effects are hampered by the development of tolerance. Furthermore, concomitant treatment with perampanel slows development of tolerance to the anticonvulsant effects of clobazam in GEPR-9 s.