title: The application of half-life in clinical decision making: Comparison of the pharmacokinetics of extended-release topiramate (USL255) and immediate-release topiramate.
abstract: For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t1/2eff) may be a more clinically relevant parameter than elimination half-life (t1/2z). 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.
  
  
  
  The t1/2zand t1/2efffor USL255 and TPM-IR were compared using data from a phase I study (N=36) of 200mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t1/2zwas investigated. To further explore the relationship between half-life and dosing, steady-state PK was simulated for USL255 and TPM-IR.
  
  
  
  As previously reported, mean t1/2zwas similar between USL255 (80.2h) and TPM-IR (82.8h); TPM-IR t1/2zwas ∼4 times longer than reported in the Topamax label (21h). In contrast, USL255 displayed a 1.5 fold longer t1/2eff(55.7 vs 37.1h for TPM-IR). When t1/2zwas calculated from 48 to 336h, values ranged from 28.8 to 82.8h. Simulated steady-state PK profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID.
  
  
  
  As expected for the same moiety, t1/2zof USL255 and TPM-IR were similar; however, the longer t1/2efffor USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPM-IR). Further, sampling duration impacted t1/2z, diminishing its predictive value for determining dose regimens; sampling-time differences may also explain t1/2zdiscrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long t1/2z, taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t1/2zmay be less clinically meaningful than t1/2eff,and using t1/2zfor some drugs may lead to erroneous conclusions regarding dosing regimens.
authors.affiliation: University of Wisconsin School of Pharmacy & Department of Neurology, Madison, WI 53705, United States. Electronic address: barry.gidal@wisc.edu.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Gidal
authors.affiliation: Upsher-Smith Laboratories, Inc. 6701 Evenstad Drive, Maple Grove, MN 55369, United States. Electronic address: annie.Clark@upsher-smith.com.
authors.forename: Annie M
authors.initials: AM
authors.lastname: Clark
authors.affiliation: Upsher-Smith Laboratories, Inc. 6701 Evenstad Drive, Maple Grove, MN 55369, United States. Electronic address: bob.anders@upsher-smith.com.
authors.forename: Bob
authors.initials: B
authors.lastname: Anders
authors.affiliation: University of Kentucky, Kentucky Neuroscience Institute, 740 South Limestone Kentucky Clinic, First floor, Wing C, Lexington, KY 40536, United States. Electronic address: f.gilliam@uky.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Gilliam
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000066491:Clinical Decision-Making; D003198:Computer Simulation; D003692:Delayed-Action Preparations; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008962:Models, Theoretical; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D000077236:Topiramate; D005632:Fructose
keywords: Antiepileptic drug; Dosing; Epilepsy; Half-life; Pharmacokinetics; Topiramate