The Application of Half-Life in Clinical Decision Making: Comparison of the Pharmacokinetics of Extended-Release Topiramate (USL255) and Immediate-Release Topiramate

Authors

Barry E. Gidal, University of Wisconsin - Madison
Annie M. Clark, Upsher-Smith Laboratories, Inc.
Bob Anders, Upsher-Smith Laboratories, Inc.
Frank Gilliam, University of KentuckyFollow

Abstract

Objective: For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t_1/2eff) may be a more clinically relevant parameter than elimination half-life (t_1/2z). 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_1/2eff for USL255 and TPM-IR were 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 t_1/2z was similar between USL255 (80.2 h) and TPM-IR (82.8 h); TPM-IR t_1/2z was ∼4 times longer than reported in the Topamax label (21 h). In contrast, USL255 displayed a 1.5 fold longer t_1/2eff (55.7 vs 37.1 h for TPM-IR). When t_1/2z 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, t_1/2z of USL255 and TPM-IR were similar; however, the longer t_1/2eff for USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPM-IR). Further, sampling duration impacted t_1/2z, diminishing its predictive value for determining dose regimens; sampling-time differences may also explain t_1/2z discrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long t_1/2z, taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t_1/2z may be less clinically meaningful than t_1/2eff, and using t_1/2z for some drugs may lead to erroneous conclusions regarding dosing regimens.

Document Type

Article

Publication Date

1-2017

Notes/Citation Information

Published in Epilepsy Research, v. 129, p. 26-32.

© 2016 The Author(s). Published by Elsevier B.V.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.eplepsyres.2016.10.020

Funding Information

The study, modeling analyses, and writing support were funded by Upsher-Smith Laboratories, Inc.

Repository Citation

Gidal, Barry E.; Clark, Annie M.; Anders, Bob; and Gilliam, Frank, "The Application of Half-Life in Clinical Decision Making: Comparison of the Pharmacokinetics of Extended-Release Topiramate (USL255) and Immediate-Release Topiramate" (2017). Neuroscience Faculty Publications. 55.
https://uknowledge.uky.edu/neurobio_facpub/55