The application of half-life in clinical decision making: Comparison of the pharmacokinetics of extended-release topiramate (USL255) and immediate-release topiramate

Objective: For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (toe) may be a more clinically relevant parameter than elimination half-life (tip,). Using topiramate as a real-life example, the objective was to compare these half-life values for immediate-and extended-release topiramate (TPM-IR and USL255, respectively) to understand how drug pharmacokinetics may impact drug dosing recommendations. Methods: The t(1/2z) and t(1/2z) for USL255 and TPM-IRwere compared using data from a phase I study (N = 36) of 200 mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t(1/2z) was investigated. To further explore the relationship between half-life and dosing, steady-state Pk was simulated for USL255 and TPM-IR. Results: As previously reported, mean tip, was similar between USL255 (80.2 h) and TPM-IR (82.8 h); TPMIR tip, was 4 times longer than reported in the Topamax label (21 h). In contrast, USL255 displayed a 1.5 fold longer t(1/2z) (55.7 vs 37.1 h for TPM-IR). When tip, was calculated from 48 to 336 h, values ranged from 28.8 to 82.8 h. Simulated steady-state Pk profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID. Significance: As expected for the same moiety, tip, of USL255 and TPM-IR were similar; however, the longer t(1/2z) for USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPMIR). Further, sampling duration impacted tip,, diminishing its predictive value for determining dose regimens; sampling-time differences may also explain tip, discrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long tip,, taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t(1/2z) may be less clinically meaningful than t(1/2z), and using tip, for some drugs may lead to erroneous conclusions regarding dosing regimens. (C) 2016 The Author(s). Published by Elsevier B.V.