Upsher-Smith Laboratories, Inc, Minneapolis, Minnesota, USA.
Epilepsia. 2011 Oct;52(10):1877-83. doi: 10.1111/j.1528-1167.2011.03183.x. Epub 2011 Jul 19.
To compare the pharmacokinetics of USL255, a once-daily extended-release (ER) formulation of topiramate (TPM), with Topamax (immediate-release TPM) in healthy subjects after oral dosing and evaluate the effect of food on USL255 bioavailability and pharmacokinetics.
This randomized, single-center, open-label, cross-over design study had three dosing periods separated by 21 days of washout between treatments. Thirty-six volunteers received single doses of USL255 (200 mg) in fasted and fed conditions and two doses of Topamax (100 mg) administered 12 h apart. TPM plasma samples were analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetic parameters were calculated by noncompartmental methods.
USL255 fasted pharmacokinetic parameters [point estimate (90% confidence interval, CI) compared to Topamax] were: relative bioavailability (F) 91.2% (84-99%), peak plasma concentration (C(max)) USL255/Topamax-ratio 59% (53-65%), time to reach C(max) (t(max)) 19.5 ± 7.2 h, accumulation ratio (R(ac)) 3.9 ± 1.2, effective half-life (t(1/2,eff)) 55.7 ± 19.9 h, terminal half-life (t(1/2,z)) 80.2 ± 14.2 h, and peak-occupancy-time (POT) 12.1 ± 4.0 h. Although the F and C(max) were unaffected by food, R(ac) and t(1/2,eff) increased to 4.9 ± 0.9, and 72.5 ± 15.4 h, respectively. In contrast to t(1/2,z,) t(1/2,eff) reflects absorption rate; therefore, USL255's t(1/2,eff) was significantly longer than Topamax's t(1/2,eff) (37.1 ± 6.5 h).
Although bioequivalent to Topamax in extent of absorption, USL255 had a slower absorption rate as reflected in its lower C(max) and longer t(max), larger POT and longer t(1/2,eff), and similar R(ac) values to that of Topamax (q12 h). This relative flat plasma profile allows for once-daily dosing with diminished fluctuations in TPM plasma levels. In addition, neither USL255's peak nor extent of plasma exposure of TPM was affected by food.
比较 USL255（一种每日一次的托吡酯（TPM）控释制剂）与 Topamax（速释 TPM）在健康受试者口服后的药代动力学，并评估食物对 USL255 生物利用度和药代动力学的影响。
这是一项随机、单中心、开放标签、交叉设计的研究，每个治疗周期之间有 21 天的洗脱期，共分为三个给药期。36 名志愿者空腹和进食状态下单次给予 USL255（200mg），12 小时后给予两次 Topamax（100mg）。通过液质联用分析法测定 TPM 血药浓度。采用非房室模型法计算药代动力学参数。
USL255 空腹药代动力学参数（与 Topamax 相比的点估计值（90%置信区间，CI））为：相对生物利用度（F）91.2%（84-99%），峰浓度（Cmax）USL255/Topamax 比值为 59%（53-65%），达峰时间（tmax）19.5±7.2 小时，蓄积比（Rac）3.9±1.2，有效半衰期（t1/2,eff）55.7±19.9 小时，终末半衰期（t1/2,z）80.2±14.2 小时，峰时浓度-时间曲线下面积（POT）12.1±4.0 小时。尽管食物不影响 F 和 Cmax，但 Rac 和 t1/2,eff 分别增加至 4.9±0.9 和 72.5±15.4 小时。与 t1/2,z 不同，t1/2,eff 反映吸收速率；因此，USL255 的 t1/2,eff 明显长于 Topamax 的 t1/2,eff（37.1±6.5 小时）。
尽管在吸收程度上与 Topamax 生物等效，但 USL255 的吸收速率较慢，表现为 Cmax 和 tmax 较低、POT 和 t1/2,eff 较大，以及与 Topamax（q12h）相似的 Rac 值。这种相对平坦的血浆曲线允许每日一次给药，减少 TPM 血浆水平的波动。此外，食物对 USL255 的 TPM 血浆峰值和暴露量均无影响。
