June 2, 2024
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In a compelling overview, D’Onofrio and colleagues summarized what is known about pharmacogenetic interactions of anti-seizure medication. Here is the summary of their paper.

Introduction

  • Research into genetic polymorphisms of drug-metabolizing enzymes for anti-seizure medications (ASMs) started in the early 2000s.
  • New ASMs prompt inquiry into the relevance of studying these polymorphisms for their management.

What is known

  • Older ASMs (phenytoin, carbamazepine, valproic acid, phenobarbital) have narrow therapeutic ranges and substantial inter-individual pharmacokinetic variability.
  • Newer ASMs like levetiracetam offer more consistent pharmacokinetic profiles.
  • ASMs metabolism primarily occurs via hepatic pathways involving enzymes like CYP2C9, CYP2C19, and CYP3A4.
  • Genetic polymorphisms in these enzymes can significantly impact drug metabolism and treatment outcomes.

Specific Enzymes and ASMs

  • CYP2C9 and CYP2C19: Impact metabolism of older ASMs; patients classified as extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs).
  • CYP3A4: Consistent expression among individuals; involved in metabolism of ASMs like carbamazepine and clonazepam.
  • EPHX1 gene: Variations affect metabolism of carbamazepine.
  • UGT enzymes: Involved in glucuronidation reactions for ASMs like lamotrigine and oxcarbazepine.

What is new

  • Brivaracetam (BRV): Metabolized by amidase and CYP2C19, with potential dose adjustments for CYP2C19 PMs.
  • Cannabidiol (CBD): Metabolized by CYP2C9, CYP2C19, and CYP3A4; the major active metabolite is 7-hydroxy-CBD.
  • Lacosamide (LCM): Metabolized by CYP2C19, CYP2C9, and CYP3A4; PMs have higher plasma levels.
  • Perampanel (PER): Metabolized by CYP3A4; genetic polymorphisms can influence plasma levels.
  • Stiripentol (STP): Inhibits multiple CYP enzymes, elevating concentrations of co-administered drugs like valproic acid.

Expert opinion

  • Pharmacogenomics can tailor epilepsy treatment, potentially preventing drug-resistant epilepsy and optimizing outcomes.
  • Despite the significance of CYP2C9 and CYP2C19, their clinical impact on ASM treatment is modest.
  • Due to its accuracy and cost-effectiveness, therapeutic drug monitoring remains a valuable tool over genetic polymorphism studies.
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