Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Novartis Pharma AG, Basel, Switzerland.
CPT Pharmacometrics Syst Pharmacol. 2020 Apr;9(4):230-237. doi: 10.1002/psp4.12502. Epub 2020 Apr 5.
Everolimus is currently approved in Europe as an adjunctive therapy for patients aged ≥ 2 years with tuberous sclerosis complex (TSC)-associated treatment-refractory partial-onset seizures, based on the EXIST-3 study (NCT01713946) results. As TSC-associated seizures can also affect children aged between 6 months and 2 years, a modeling and simulation (M&S) approach was undertaken to extrapolate exposure (trough plasma concentration (C )) after a dose of 6 mg/m and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp was developed to predict C in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short-term and long-term efficacy in adults (for validation) and in children, respectively. Based on the results of the M&S study, everolimus at the dose of 6 mg/m is anticipated to be an efficacious treatment in children 6 months to 2 years of age (up to 77.8% RSF) with concentrations within the recommended target range.
依维莫司目前在欧洲被批准用于治疗 2 岁及以上伴结节性硬化症相关治疗抵抗性部分发作性癫痫的患者，其适应证是基于 EXIST-3 研究（NCT01713946）的结果。由于结节性硬化症相关癫痫也可能影响 6 个月至 2 岁的儿童，因此采用建模与模拟（M&S）方法外推 6mg/m 剂量后的暴露量（谷浓度[C ]）和癫痫发作频率降低（RSF）。使用 Simcyp 开发了一个基于生理学的药代动力学模型来预测成人和儿科患者的 C ，然后使用群体药代动力学模型和线性混合效应模型来预测成人（验证）和儿童的短期和长期疗效。基于 M&S 研究的结果，预计 6 个月至 2 岁儿童的 6mg/m 剂量的依维莫司治疗具有疗效（RSF 高达 77.8%），且浓度处于推荐的目标范围内。
