Gidal Barry E, Mintzer Scott, Schwab Matthias, Schutz Ralph, Kharidia Jahnavi, Blum David, Grinnell Todd, Sunkaraneni Soujanya
School of Pharmacy and Department of Neurology, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA.
Thomas Jefferson University, 909 Walnut Street, Philadelphia, PA 19107, USA.
Epilepsy Res. 2017 Sep;135:64-70. doi: 10.1016/j.eplepsyres.2017.05.005. Epub 2017 May 18.
Patients with partial-onset seizures and comorbid cardiovascular disease may concomitantly receive eslicarbazepine acetate (ESL), an antiepileptic drug, and rosuvastatin, an HMG-CoA reductase inhibitor. This study evaluated the effect of multiple-dose ESL on the pharmacokinetic (PK) parameters of a single dose of rosuvastatin in healthy subjects.
This was a Phase I, single-center, fixed-sequence, open-label study. Healthy subjects received two treatments, in sequence. Treatment A: a single 40mg oral dose of rosuvastatin on Day 1, followed by a washout period (Days 1-4); treatment B: titration of ESL (400-800mg once daily) on Days 5-18, followed by ESL 1200mg once daily on Days 19-35, with a single dose of rosuvastatin (40mg) on Day 32. Subjects then entered a 2-week follow-up period. Plasma concentrations of rosuvastatin were quantified for PK analyses. Safety and tolerability were assessed throughout the study.
Thirty-three healthy subjects were enrolled and 30 completed the study. Mean rosuvastatin (standard deviation) t was similar when rosuvastatin was used concomitantly with ESL and when it was used alone (26.5 [16.3]h, and 22.4 [9.5]h, respectively). The geometric least squares mean ratios (90% confidence intervals) of rosuvastatin exposure levels between rosuvastatin used concomitantly with ESL and rosuvastatin used alone were as follows: C, 64.0% (55.9-73.3%); AUC, 63.0% (57.1-69.4%); and AUC, 60.9% (55.2-67.1%). Concomitant use of ESL and rosuvastatin was generally well tolerated.
Rosuvastatin exposure was 36-39% lower with steady-state administration of ESL, potentially due to reduced oral bioavailability of rosuvastatin. Consequently, when rosuvastatin is used with ESL, a rosuvastatin dose adjustment may be necessary if a clinically significant change in lipids is noted.
部分性发作且合并心血管疾病的患者可能会同时服用抗癫痫药物醋酸艾司利卡西平（ESL）和HMG-CoA还原酶抑制剂瑞舒伐他汀。本研究评估了多剂量ESL对健康受试者单剂量瑞舒伐他汀药代动力学（PK）参数的影响。
这是一项I期单中心、固定顺序、开放标签研究。健康受试者按顺序接受两种治疗。治疗A：第1天口服单剂量40mg瑞舒伐他汀，随后为洗脱期（第1 - 4天）；治疗B：第5 - 18天滴定ESL（每日一次400 - 800mg），随后在第19 - 35天每日一次服用1200mg ESL，在第32天服用单剂量瑞舒伐他汀（40mg）。受试者随后进入为期2周的随访期。对瑞舒伐他汀的血浆浓度进行定量以进行PK分析。在整个研究过程中评估安全性和耐受性。
33名健康受试者入组，30名完成研究。瑞舒伐他汀与ESL同时使用时和单独使用时的平均（标准差）t相似（分别为26.5[16.3]小时和22.4[9.5]小时）。瑞舒伐他汀与ESL同时使用和单独使用时瑞舒伐他汀暴露水平的几何最小二乘均值比（90%置信区间）如下：Cmax，64.0%（55.9 - 73.3%）；AUC0 - t，63.0%（57.1 - 69.4%）；和AUC0 - ∞，60.9%（55.2 - 67.1%）。ESL和瑞舒伐他汀同时使用一般耐受性良好。
ESL稳态给药时瑞舒伐他汀的暴露量降低了36 - 39%，这可能是由于瑞舒伐他汀的口服生物利用度降低所致。因此，当瑞舒伐他汀与ESL合用时，如果发现血脂有临床显著变化，可能需要调整瑞舒伐他汀剂量。
