کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5628768 | 1579894 | 2017 | 7 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: The application of half-life in clinical decision making: Comparison of the pharmacokinetics of extended-release topiramate (USL255) and immediate-release topiramate The application of half-life in clinical decision making: Comparison of the pharmacokinetics of extended-release topiramate (USL255) and immediate-release topiramate](/preview/png/5628768.png)
- t1/2z may not adequately describe drug accumulation and distribution for some drugs.
- t1/2eff may be more appropriate; it describes drug-loss rate over dosing interval.
- For IR and XR topiramate, t1/2z was similar but t1/2eff was 1.5Ã longer for XR.
- Steady-state simulations predicted reduced fluctuation for XR topiramate vs IR.
ObjectiveFor 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.MethodsThe t1/2z and t1/2eff for USL255 and TPM-IR were compared using data from a phase I study (NÂ =Â 36) of 200Â mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t1/2z was investigated. To further explore the relationship between half-life and dosing, steady-state PK was simulated for USL255 and TPM-IR.ResultsAs previously reported, mean t1/2z was similar between USL255 (80.2Â h) and TPM-IR (82.8Â h); TPM-IR t1/2z was â¼4 times longer than reported in the Topamax label (21Â h). In contrast, USL255 displayed a 1.5 fold longer t1/2eff (55.7 vs 37.1Â h for TPM-IR). When t1/2z was calculated from 48 to 336Â h, values ranged from 28.8 to 82.8Â h. Simulated steady-state PK profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID.SignificanceAs expected for the same moiety, t1/2z of USL255 and TPM-IR were similar; however, the longer t1/2eff for 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 t1/2z discrepancy 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 t1/2z may be less clinically meaningful than t1/2eff, and using t1/2z for some drugs may lead to erroneous conclusions regarding dosing regimens.
Journal: Epilepsy Research - Volume 129, January 2017, Pages 26-32