BACKGROUND ACT-709478 is a selective, orally available T-type calcium channel blocker being studied as a potential new treatment in epilepsy. ACT-709478 had previously been investigated in a single-ascending dose study up to a dose of 400 mg. OBJECTIVES The aim of this study was to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of ACT-709478. In addition, the drug-drug interaction potential of multiple doses of ACT-709478 with the cytochrome P450 3A4 substrate midazolam was investigated. METHODS This double-blind, placebo-controlled, randomized study included 46 healthy male and female subjects. Ascending multiple oral doses of ACT-709478 were administered to 10 (cohorts 1-2) or 12 (cohorts 3-4) subjects (two taking placebo per cohort). In cohorts 1-2, 30 or 10 mg ACT-709478 was administered once daily for 12 days. An up-titration regimen was used in cohorts 3-4 with administration of 10, 30, and 60 mg for 7 days each in both cohorts and an additional dose level of 100 mg ACT-709478 once daily for 8 days in cohort 4. Single doses of midazolam were administered at baseline and concomitantly to 60 mg and 100 mg ACT-709478 in cohort 4. Blood sampling for pharmacokinetic evaluations and safety assessments (clinical laboratory, vital signs, adverse events, and electrocardiogram) were performed regularly. Holter electrocardiograms were recorded at baseline and for 24 h at steady state and central nervous system effects were assessed with pharmacodynamic tests at baseline and steady state. RESULTS ACT-709478 was absorbed with a time to reach the maximum plasma concentration of 3.5-4.0 h and eliminated with a half-life of 45-53 h. Steady state was reached after 5-7 days of dosing and exposure increased dose-proportionally. An accumulation index of approximately three fold was observed in cohorts 1 and 2. Exposure to midazolam was lower upon concomitant administration of 60 and 100 mg ACT-709478 compared to midazolam alone while the half-life and time to reach the maximum plasma concentration of midazolam remained unchanged, suggesting a weak induction at the gastrointestinal but not hepatic level. Pharmacokinetic parameters of 1-hydroxymidazolam were not affected by ACT-709478 administration. The most frequent adverse events were dizziness, somnolence, and headache. A tolerability signal was detected in cohort 1 (30 mg once daily); therefore, the dose was decreased to 10 mg once daily in cohort 2. The subsequently established up-titration regimen, starting with 10 mg once daily, considerably improved tolerability. Multiple doses up to 100 mg once daily were well tolerated. No treatment-related effects were detected on vital signs, clinical laboratory tests, Holter electrocardiogram variables, or in the pharmacodynamic tests. CONCLUSIONS ACT-709478 exhibits good tolerability up to 100 mg once daily using an up-titration regimen and pharmacokinetic properties that support further clinical investigations. A weak induction of gastrointestinal cytochrome P450 3A4 activity was observed, unlikely to be of clinical relevance. CLINICALTRIALS. GOV IDENTIFIER NCT03165097.

中文翻译：

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在健康受试者中进行多剂量研究，以评估T型钙通道阻滞剂ACT-709478（一种潜在的新型抗癫痫药）的药代动力学，耐受性和CYP3A4相互作用的潜力。

背景技术ACT-709478是一种选择性的，口服可利用的T型钙通道阻滞剂，正在研究作为癫痫的潜在新疗法。ACT-709478以前曾在单次剂量研究中研究过，剂量一直到400 mg。目的本研究的目的是研究多剂量ACT-709478的安全性，耐受性，药代动力学和药效学。此外，还研究了多剂量ACT-709478与细胞色素P450 3A4底物咪达唑仑的药物-药物相互作用潜力。方法该双盲，安慰剂对照，随机研究包括46位健康的男性和女性受试者。对10名（第1-2组）或12名（第3-4组）受试者（每组两名服用安慰剂）给予多剂量的ACT-709478口服剂量。在群组1-2中，每天一次30或10 mg ACT-709478，持续12天。在第3-4组中使用滴定方案，两个组分别给药10、30和60 mg，共7天，在第4组中，每天一次附加剂量水平为100 mg ACT-709478，共8天。基线时给予咪达唑仑剂量，并在第4组中同时给予60 mg和100 mg ACT-709478。定期进行血液采样以进行药代动力学评估和安全性评估（临床实验室，生命体征，不良事件和心电图）。在基线时记录动态心电图，在稳态下记录24 h，并在基线和稳态下通过药效学测试评估中枢神经系统的作用。结果ACT-709478的吸收时间达到最大血浆浓度3.5-4。0小时后消除，半衰期为45-53小时。给药5-7天后达到稳定状态，且剂量成比例增加。在人群1和2中观察到大约3倍的累积指数。与单独使用咪达唑仑相比，同时给予60和100 mg ACT-709478时，与咪达唑仑的接触率更低，而达到咪达唑仑最高血浆浓度的半衰期和时间保持不变，表明在胃肠道的诱导较弱，但在肝水平上没有。1-羟基咪达唑仑的药代动力学参数不受ACT-709478管理的影响。最常见的不良事件是头晕，嗜睡和头痛。在队列1中检测到耐受性信号（每天一次30 mg）；因此，在第2组中，该剂量降至每天一次10 mg。随后建立的向上滴定方案，从每天一次10 mg开始，大大提高了耐受性。每天一次最多100 mg的多次剂量耐受良好。在生命体征，临床实验室测试，心电图心电图变量或药效学测试中未检测到与治疗相关的作用。结论ACT-709478每天使用一次滴定方案和药代动力学特性可表现出高达100 mg的良好耐受性，从而支持进一步的临床研究。观察到对胃肠道细胞色素P450 3A4活性的诱导较弱，这不太可能具有临床意义。临床试验。政府识别码NCT03165097。在生命体征，临床实验室测试，心电图心电图变量或药效学测试中未检测到与治疗相关的作用。结论ACT-709478每天使用一次滴定方案和药代动力学特性可表现出高达100 mg的良好耐受性，从而支持进一步的临床研究。观察到对胃肠道细胞色素P450 3A4活性的诱导较弱，这不太可能具有临床意义。临床试验。政府识别码NCT03165097。在生命体征，临床实验室测试，心电图心电图变量或药效学测试中未检测到与治疗相关的作用。结论ACT-709478每天使用一次滴定方案和药代动力学特性可表现出高达100 mg的良好耐受性，从而支持进一步的临床研究。观察到对胃肠道细胞色素P450 3A4活性的诱导较弱，这不太可能具有临床意义。临床试验。政府识别码NCT03165097。观察到对胃肠道细胞色素P450 3A4活性的诱导较弱，这不太可能具有临床意义。临床试验。政府识别码NCT03165097。观察到对胃肠道细胞色素P450 3A4活性的诱导较弱，这不太可能具有临床意义。临床试验。政府识别码NCT03165097。