Mid-Atlantic Epilepsy and Sleep Center, 6410 Rockledge Dr, Suite 610, Bethesda, MD 20817, USA.
Lundbeck, 6 Parkway North Suite 200, Deerfield, IL 60015, USA.
Epilepsy Behav. 2019 Oct;99:106459. doi: 10.1016/j.yebeh.2019.106459. Epub 2019 Sep 10.
The goal of this study was to characterize the drug-drug interactions between clobazam and 2 antiseizure drugs, cannabidiol and stiripentol, for treatment of refractory seizures through the use of pharmacokinetic modeling.
A population pharmacokinetic/pharmacodynamic model was developed to characterize the combined effect of clobazam and its active metabolite, N-desmethylclobazam (i.e., N-clobazam), on seizure protection in patients with Lennox-Gastaut syndrome using data from the phase 3 CONTAIN trial. Drug-drug interactions between clobazam and cannabidiol were examined by comparing model-generated data to data from a study of 13 patients taking concomitant clobazam and cannabidiol. Modeling data were also descriptively compared with studies of patients administered both clobazam and stiripentol. Sedation-related adverse events from CONTAIN were analyzed to determine the exposure-somnolence relationship of clobazam.
Exposure-efficacy analysis from the pharmacokinetic/pharmacodynamic model using CONTAIN data indicated that clobazam (half-maximal effective concentration [EC], 303 ng/mL) was 3 times more potent than N-clobazam (EC, 899 ng/mL). After administration of clobazam, when both clobazam and N-clobazam concentrations were each 1 to 2 times the EC value (clobazam dose, 20 mg), 70.0%-74.9% seizure protection was predicted; when concentrations were >2 times the EC value (clobazam dose, 40 mg), 74.0%-96.9% seizure protection was predicted. Generalized additive model analyses demonstrated decreased seizure probability with higher plasma concentration of clobazam. Coadministration of stiripentol and clobazam resulted in increased respective median plasma concentrations of clobazam and N-clobazam (1.1-1.2 times and 5.2-8.2 times) compared with administration of placebo and clobazam. Probability of somnolence significantly increased with age and higher N-clobazam plasma concentration.
Awareness of drug-drug interactions between clobazam and cannabidiol is needed when adding cannabidiol or stiripentol to a regimen of clobazam or vice versa. Based upon our population pharmacokinetic/pharmacodynamic model, we predict that an increase in N-clobazam levels, which patient data show may enhance efficacy and/or make adverse events such as somnolence more likely.
本研究旨在通过药代动力学建模来描述氯巴占与两种抗癫痫药物（大麻二酚和司替戊醇）之间的药物相互作用，以治疗难治性癫痫。
利用 3 期 CONTAIN 试验中 Lennox-Gastaut 综合征患者的药物疗效数据，建立了一个群体药代动力学/药效学模型，以描述氯巴占及其活性代谢物 N-去甲基氯巴占（即 N-氯巴占）对癫痫保护的联合作用。通过比较模型生成的数据与同时接受氯巴占和大麻二酚治疗的 13 例患者的研究数据，考察了氯巴占与大麻二酚之间的药物相互作用。还对接受氯巴占和司替戊醇联合治疗的患者进行了描述性比较。对 CONTAIN 的镇静相关不良事件进行分析，以确定氯巴占的暴露-嗜睡关系。
使用 CONTAIN 数据进行的药代动力学/药效学模型的暴露-疗效分析表明，氯巴占（半最大有效浓度 [EC]，303ng/mL）的效力是 N-氯巴占（EC，899ng/mL）的 3 倍。给予氯巴占后，当氯巴占和 N-氯巴占浓度分别为 EC 值的 1 到 2 倍（氯巴占剂量，20mg）时，预测到 70.0%-74.9%的癫痫发作保护；当浓度超过 EC 值的 2 倍（氯巴占剂量，40mg）时，预测到 74.0%-96.9%的癫痫发作保护。广义加性模型分析表明，随着氯巴占血浆浓度的升高，癫痫发作的概率降低。与安慰剂和氯巴占联合治疗相比，同时给予司替戊醇和氯巴占可使氯巴占和 N-氯巴占的中位血浆浓度分别增加 1.1-1.2 倍和 5.2-8.2 倍。嗜睡的可能性随着年龄的增长和 N-氯巴占血浆浓度的升高而显著增加。
在氯巴占治疗方案中添加大麻二酚或司替戊醇或反之，需要了解氯巴占与大麻二酚之间的药物相互作用。基于我们的群体药代动力学/药效学模型，我们预测 N-氯巴占水平的升高可能会增强疗效，并且可能使不良反应（如嗜睡）更有可能发生，而患者数据表明这可能会增强疗效。
