Pharmacodynamics and common drug-drug interactions of the third-generation antiepileptic drugs

ABSTRACT

Introduction: Anticonvulsants that belong to the third generation are considered as ‘newer’ antiepileptic drugs, including: eslicarbazepine acetate, lacosamide, perampanel, brivaracetam, rufinamide and stiripentol.

Areas covered: This article reviews pharmacodynamics (i.e. mechanisms of action) and clinically relevant drug-drug interactions of the third-generation antiepileptic drugs.

Expert opinion: Newer antiepileptic drugs have mechanisms of action which are not shared with the first and the second generation anticonvulsants, like inhibition of neurotransmitters release, blocking receptors for excitatory amino acids and new ways of sodium channel inactivation. New mechanisms of action increase chances of controlling forms of epilepsy resistant to older anticonvulsants. Important advantage of the third-generation anticonvulsants could be their little propensity for interactions with both antiepileptic and other drugs observed until now, making prescribing much easier and safer. However, this may change with new studies specifically designed to discover drug-drug interactions. Although the third-generation antiepileptic drugs enlarged therapeutic palette against epilepsy, 20–30% of patients with epilepsy is still treatment-resistant and need new pharmacological approach. There is great need to explore all molecular targets that may directly or indirectly be involved in generation of seizures, so a number of candidate compounds for even newer anticonvulsants could be generated.

KEYWORDS:

• Third-generation anticonvulsants
• mechanism of action
• drug-drug interactions
• therapy-resistant epilepsy

Article highlights

• ‘Newer’ antiepileptic drugs are also designated as the third-generation anticonvulsants, including: eslicarbazepine acetate, lacosamide, perampanel, brivaracetam and rufinamide.

• Mechanisms of action of the third-generation anticonvulsants are inhibition of neurotransmitters release, blocking receptors for excitatory amino acids and new ways of sodium channel inactivation.

• The third-generation anticonvulsants were rarely associated in the past with clinically significant drug-drug interactions; however, this probably more reflects limited research in this area done so far (pharmaceutical companies do not have major interest in publishing on drug-drug interactions) than true safety profile of these drugs.

• Majority of the observed interactions are of pharmacokinetic type and their clinical significance is uncertain.

• Adequately powered observational studies are necessary to make true estimate of risk imposed by drug-drug interactions, which will be of great help in everyday treatment of patients with epilepsy.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article was partially supported by the grant No 175007 by Serbian Ministry of Education, Science and Technology.