两个开放标签,1期研究(NCT05064449,NCT05098041)研究了CYP3A抑制(通过伊曲康唑)的作用,UGT1A9抑制(通过甲芬那酸),和CYP3A诱导(通过利福平)对seticlestat及其代谢物M-I和M3的药代动力学的影响。在这两项研究的第一阶段,参与者接受单剂量seticlestat300mg.在第2阶段,参与者在第1-11天接受伊曲康唑,在第5天接受300mg索非尼那酸(伊曲康唑/甲芬那酸研究;第1部分);在第1-7天接受甲芬那酸,在第2天接受300mg索非尼那酸(伊曲康唑/甲芬那酸研究;第2部分);或在第1-13天接受利福平,28名健康成年人参加了伊曲康唑/甲芬那酸研究(每个部分14人),15人参加了利福平研究(平均年龄,38.1-40.7岁;男性,79-93%)。对于最大观察浓度,seticlestat+伊曲康唑的几何平均比率(GMR),甲芬那酸,或利福平单独使用seticlestat为116.6%,107.3%和13.2%,分别,seticlestat;10.7%,118.0%和266.1%,分别,对于M-I来说,和104.6%,88.2%和66.6%,分别,对于M3。对于从时间0到无穷大的曲线下面积,相应的GMR为124.0%,100.6%,和16.4%;13.3%,117.0%,M-I为180.8%;1203%,92.6%,M3为58.4%。Soticlestat可以与强CYP3A和UGT1A9抑制剂一起施用,但不是强CYP3A诱导剂(除了抗癫痫药物,这将在正在进行的3期研究中进一步评估)。在两项研究中,所有因治疗引起的不良事件均为轻度或中度.ClinicalTrials.gov:NCT05064449,NCT05098041意义声明这些药物-药物相互作用研究提高了我们对使用CYP3A抑制剂治疗的患者在seticlestat暴露中可能出现的潜在变化的理解,UGT1A9抑制剂,或CYP3A诱导剂。该结果建立在先前发表的seticlestat研究的基础上,并提供了重要的信息来帮助指导临床实践。Soticlestat已显示出2期阳性结果,目前正处于3期开发中,用于治疗Dravet综合征和Lennox-Gastaut综合征患者的癫痫发作。
Two open-label, phase 1 studies (NCT05064449, NCT05098041) investigated the effects of cytochrome P450 (CYP) 3A inhibition (via itraconazole), UDP glucuronosyltransferase (UGT) 1A9 inhibition (via mefenamic acid), and CYP3A induction (via rifampin) on the pharmacokinetics of soticlestat and its metabolites M-I and M3. In period 1 of both studies, participants received a single dose of soticlestat 300 mg. In period 2, participants received itraconazole on days 1-11 and soticlestat 300 mg on day 5 (itraconazole/mefenamic acid study; part 1); mefenamic acid on days 1-7 and soticlestat 300 mg on day 2 (itraconazole/mefenamic acid study; part 2); or rifampin on days 1-13 and soticlestat 300 mg on day 11 (rifampin study). Twenty-eight healthy adults participated in the itraconazole/mefenamic acid study (14 per part) and 15 participated in the rifampin study (mean age, 38.1-40.7 years; male, 79-93%). For maximum observed concentration, the geometric mean ratios (GMRs) of soticlestat + itraconazole, mefenamic acid, or rifampin to soticlestat alone were 116.6%, 107.3%, and 13.2%, respectively, for soticlestat; 10.7%, 118.0%, and 266.1%, respectively, for M-I, and 104.6%, 88.2%, and 66.6%, respectively, for M3. For area under the curve from time 0 to infinity, the corresponding GMRs were 124.0%, 100.6%, and 16.4% for soticlestat; 13.3%, 117.0%, and 180.8% for M-I; and 120.3%, 92.6%, and 58.4% for M3. Soticlestat can be administered with strong CYP3A and UGT1A9 inhibitors, but not strong CYP3A inducers (except for antiseizure medications, which will be further evaluated in ongoing phase 3 studies). In both studies, all treatment-emergent adverse events were mild or moderate. SIGNIFICANCE STATEMENT: These drug-drug interaction studies improve our understanding of the potential changes that may arise in soticlestat exposure in patients being treated with CYP3A inhibitors, UGT1A9 inhibitors, or CYP3A inducers. The results build on findings from previously published soticlestat studies and provide important information to help guide clinical practice. Soticlestat has shown positive phase 2 results and is currently in phase 3 development for the treatment of seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome.