Development and validation of a pharmacokinetic tool to convert random topiramate concentrations to standardized...

Topiramate is sometimes used in patients with bipolar disorder (BD), though off-label, warranting therapeutic drug monitoring (TDM) for safety. Guidelines recommend trough-level sampling (12-16h post-dose), but random levels are common, complicating interpretation. A tool to convert random topiramate concentrations to a standardized trough equivalent is lacking.

To develop and validate a pharmacokinetic (PK) tool for estimating the standardized trough concentration at 14h post-dose (C₁₄) from a random sample in patients receiving topiramate.

A conversion model was derived using a one-compartment model with population PK parameters for immediate-release topiramate (elimination half-life = 25h, time-to-peak = 3h). A conversion coefficient (Kt) table was generated. The tool was validated against 183 paired TDM samples from inpatients with BD on stable topiramate monotherapy, using the measured C₁₄ as reference. Reliability, agreement, and accuracy were assessed via intraclass correlation coefficient (ICC), Bland-Altman analysis, and mean absolute percentage error (MAPE).

The tool demonstrated excellent reliability (ICC = 0.92, 95% CI: 0.90-0.94) and agreement (mean bias = +0.008 μg/mL). Predictive accuracy was high (MAPE = 6.3%), with 97.3% of estimates having an absolute error <15%. Performance was consistent across pharmacokinetic phases and subgroups (age, dose).

This preliminary PK conversion tool reliably estimates the standardized trough concentration of immediate-release topiramate from random TDM levels. It could potentially aid safety monitoring by improving the interpretation of non-standard samples, though its clinical utility requires prospective external validation and linkage to patient outcomes.