Pfizer Inc, New York, NY 10017, USA.
Eur J Clin Pharmacol. 2010 Feb;66(2):171-6. doi: 10.1007/s00228-009-0748-y. Epub 2009 Nov 14.
Diurnal variation can affect drug pharmacokinetics. Fesoterodine is a new antimuscarinic drug for the treatment of overactive bladder (OAB). We estimated the relative bioavailability of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine, following nighttime and daytime administration.
In this randomized, open-label, two-period, two-treatment crossover, single-dose study, healthy subjects received daytime and nighttime oral dosing of fesoterodine 8-mg sustained-release tablets, separated by a minimum 60-h washout period. Blood samples for 5-HMT PK determination were collected before dosing and at specified intervals up to 48 h postdose. Safety was assessed by adverse event (AE) reports.
Fourteen subjects completed the study. Plasma concentration versus time profiles (AUC) of 5-HMT were similar for daytime and nighttime dosing. Mean AUC(infinity) 5-HMT values were 47.9 and 51.4 ng h/mL for nighttime and daytime dosing, respectively; the mean time to reach maximum concentration (C(max)) values were 3.9 and 5.0 ng/mL, respectively. Nighttime versus daytime AUC(infinity) and C(max) ratios of 5-HMT were 93 and 79%, respectively; 90% confidence intervals (CIs) indicated equivalence for AUC(infinity) but not for C(max). The median time to reach maximum concentration (T(max)) was 5.0 h for both dosing regimens, and the mean terminal elimination half-life (T((1/2))) was 5.9 and 5.7 h for nighttime and daytime dosing, respectively. Seven treatment-related AEs, most commonly headache, occurred in five subjects.
The AUC values for daytime and nighttime administration of fesoterodine were equivalent. The 21% reduction in the C(max) for nighttime dosing is unlikely to be clinically relevant. No safety issues were apparent. These results support both daytime and nighttime administration of fesoterodine for OAB treatment.
昼夜变化会影响药物的药代动力学。非索罗定是一种新的用于治疗膀胱过度活动症（OAB）的抗毒蕈碱药物。我们评估了非索罗定的活性代谢产物 5-羟甲基托特罗定（5-HMT）在夜间和白天给药后的相对生物利用度。
在这项随机、开放标签、两周期、两处理交叉、单次剂量研究中，健康受试者分别在白天和夜间口服给予非索罗定 8 毫克缓释片，两次给药之间最少间隔 60 小时。在给药前和给药后指定的时间间隔内采集 5-HMT PK 测定的血样，直至 48 小时。通过不良事件（AE）报告评估安全性。
14 名受试者完成了研究。5-HMT 的血浆浓度-时间曲线（AUC）在白天和夜间给药时相似。5-HMT 的 AUC（∞）均值分别为夜间和白天给药时的 47.9 和 51.4ng h/mL；C(max)值的均值分别为 3.9 和 5.0ng/mL。5-HMT 的夜间与白天 AUC（∞）和 C(max)比值分别为 93%和 79%；90%置信区间（CI）表明 AUC（∞）等效，但 C(max)不等效。达到最大浓度（T(max)）的中位数时间对于两种给药方案均为 5.0 小时，平均终末消除半衰期（T（1/2））分别为夜间和白天给药时的 5.9 和 5.7 小时。两种给药方案均有 7 例与治疗相关的 AE，最常见的是头痛，发生在 5 名受试者中。
非索罗定白天和夜间给药的 AUC 值相当。夜间给药时 C(max)降低 21%不太可能具有临床相关性。没有出现安全性问题。这些结果支持膀胱过度活动症的非索罗定治疗可以在白天和夜间给药。
