Topiramate dosage optimization for effective antiseizure management via population pharmacokinetic modeling

ObjectiveDespite the suggested topiramate serum level of 5-20 mg/L, numerous institutions have observed substantial drug response at lower levels. We aim to investigate the correlation between topiramate serum levels, drug responsiveness, and adverse events to establish a more accurate and tailored therapeutic range.MethodsWe retrospectively analyzed clinical data collected between January 2017 and January 2022 at Seoul National University Hospital. Drug responses to topiramate were categorized as "insufficient" or "sufficient" by reduction in seizure frequency >= 50%. A population pharmacokinetic model estimated serum levels from spot measurements. ROC curve analysis determined the optimal cutoff values.ResultsA total of 389 epilepsy patients were reviewed having a mean dose of 178.4 +/- 117.9 mg/day and the serum level, 3.9 +/- 2.8 mg/L. Only 5.6% samples exhibited insufficient response, with a mean serum level of 3.6 +/- 2.5 mg/L while 94.4% demonstrated sufficient response, with a mean 4.0 +/- 2.8 mg/L, having no statistical significance. Among the 69 reported adverse events, logistic regression analysis identified a significant association between ataxia and serum concentration (p = 0.04), with an optimal cutoff value of 6.5 mg/L.InterpretationThis study proposed an optimal therapeutic concentration for topiramate based on patients' responsiveness to the drug and the incidence of adverse effects. We recommended serum levels below 6.5 mg/L to mitigate the risk of ataxia-related side effects while dose elevation was found unnecessary for suboptimal responders, as the drug's effectiveness plateaus at minimal doses.