Abstracts

Rationale: When deciding on a drug regimen, clinicians frequently use elimination half-life (t_1/2z) as the primary parameter to determine dosing frequency. t_1/2z, the time interval over which drug concentration in the body is decreased by one-half, describes drug loss after drug absorption and redistribution and can be used to predict the time needed to achieve steady state. While drug information sources typically provide this value, the use of t_1/2z to determine dosing frequency and predict drug accumulation may not always be appropriate because most drugs, including topiramate (TPM), distribute into multiple tissue compartments, and measurements reveal multi-exponential disposition (ie, more than 1 half-life). This can be problematic for extended-release (XR) formulations, because t_1/2z may not accurately predict drug concentration decline during a dosing interval. For example, XR TPM (USL255; Qudexy™ XR) has a slower rate of oral absorption vs immediate-release TPM (TPM-IR; Topamax^®). We postulate a more appropriate parameter to predict multidose drug accumulation and guide determination of the time between TPM doses may be effective half-life (t_1/2eff), which characterizes the rate of drug loss from the body over a dosing interval. The objective of this analysis was to compare t_1/2z and t_1/2eff of XR with IR TPM. Methods: A Phase 1, randomized (N=36), open-label, crossover study evaluated single-dose USL255 200 mg and 2 doses of TPM-IR 100 mg (q12h). Plasma concentrations were measured up to 336 h following treatment using an assay with 10 ng/mL lower limit of quantification (LLOQ). Pharmacokinetic (PK) parameters, including t_1/2z, t_1/2eff, and time to maximum plasma concentration (T_max, an indirect measure of absorption), were evaluated. t_1/2z=ln2/λz was calculated using the slope of the terminal phase (λz) whereas t_1/2eff=τ*ln2/ln[Rac/(Rac-1)] accounted for both the dosing interval (τ) and accumulation index (Rac). Results: t_1/2z was similar for USL255 and TPM-IR (80 vs 83 h); however, t_1/2eff was markedly different, with USL255 displaying a 1.5-fold increase over TPM-IR (56 vs 37 h). USL255 had a longer T_max than TPM-IR, indicating slower absorption. The TPM-IR t_1/2z observed in this study is longer than that reported in the Topamax label (83 vs 21 h), likely due to the longer sampling time (336 vs 32 h) and sensitivity of the PK assays (10 vs 500 ng/mL LLOQ). Conclusions: t_1/2z of XR and IR TPM were similar, as expected for a PK measure related to the active moiety. This exemplifies how t_1/2z may result in an over prediction of the appropriate dosing interval, and lead to the assumption that changes in plasma concentration over 24 h are similar between IR and XR formulations. In contrast, t_1/2eff was shorter than t_1/2z for both formulations. USL255 displayed a longer t_1/2eff versus TPM-IR, predictable for a measure that takes into account absorption rate. These data demonstrate that t_1/2eff may be more clinically relevant than t_1/2z, particularly for XR drugs, and preferred when constructing a dosage regimen. Supported by Upsher-Smith Laboratories, Inc.