JAMA Netw Open

What’s the real impact of pharmacogenetic variants on antiseizure drug plasma levels?

August 12, 2024

CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with clinically relevant increases in phenytoin plasma concentrations, a finding that could inform genotype-based dosing guidelines and highlight the potential need for preemptive genotyping in phenytoin therapy. Conversely, numerous pharmacogenetic variants previously associated with the metabolism of valproate, carbamazepine, and lamotrigine exhibited only marginal, if any, clinical relevance.

Data from 98 studies including 12,543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for the following:

• Phenytoin: by 46% in CYP2C9 intermediate metabolizers, 20% in CYP2C19 intermediate metabolizers, and 39% in CYP2C19 poor metabolizers
• Valproate: by 12% in CYP2C9 intermediate metabolizers, 12% in CYP2C19 intermediate metabolizers, and 20% in CYP2C19 poor metabolizers
• Carbamazepine: 12% in CYP3A5 poor metabolizers.

Source:

Milosavljevic F, et al. (2024, August 1). JAMA Netw Open. Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs: A Systematic Review and Meta-Analysis. https://pubmed.ncbi.nlm.nih.gov/39115847/