Is Half-Life a Clinically Relevant Measure for Extended-Release Drugs? Data Comparing Immediate- and Extended-Release Topiramate (USL255; Qudexy™ XR) (P1.249)

Objective: Describe different half-life measures and compare immediate- and extended-release topiramate (TPM-IR [Topamax®] and USL255 [Qudexy™ XR]) Background: Clinicians frequently use elimination half-life (t 1/2z ; time to decrease drug concentration by half after absorption and redistribution) to determine dosing frequency and time to steady state. However, t 1/2z may not always be appropriate because XR formulations can exhibit prolonged absorption, and most drugs, including topiramate, redistribute into multiple tissue compartments. A more appropriate parameter to predict multidose drug accumulation may be effective half-life (t 1/2eff ), rate of drug loss over a dosing interval. Design/Methods: Half-lives were compared using data from a phase 1, randomized (N=36), open-label, single-dose crossover study of 200mg USL255 QD and 100mg TPM-IR BID. Plasma concentrations were measured for 336h using an assay with 10ng/mL lower limit of quantification. Pharmacokinetic parameters included t 1/2z , t 1/2eff , and time to maximum plasma concentration (T max ). t 1/2z was calculated using the terminal phase slope whereas t 1/2eff accounted for dosing interval and accumulation index. Results: t 1/2z was similar for USL255 (80h) and TPM-IR (83h); however, t 1/2eff was markedly different (56 vs 37h). USL255 T max was longer than TPM-IR, indicating slower absorption. TPM-IR t 1/2z observed here is longer than reported in the Topamax product information (83 vs 21h), likely due to longer sampling time and increased assay sensitivity. Conclusions: Despite differences in recommended dosing, t 1/2z of USL255 and TPM-IR were similar, which may lead to the assumption that changes in plasma concentration over 24h are similar. In contrast, USL255 displayed a longer t 1/2eff versus TPM-IR, predictable for a measure that takes into account absorption. This difference in t 1/2eff better reflects the once- vs twice-daily dosing that is recommended for USL255 and TPM-IR. Though half-life is a commonly recognized drug-elimination parameter, t 1/2eff may be more clinically relevant for XR drugs. Study Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Gidal has received personal compensation for activities with GlaxoSmithKline, UCB Pharma, Eisai, Sunovian, and Upsher Smith Laboratories, Inc. as a consultant and/or speaker. Dr. Gidal has received research support from GlaxoSmithKline and UCB Pharma. Dr. Clark has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee. Dr. Anders has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee.