Background

Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study’s results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies.

Methods

Initial application of the adult model suggested that a 75 mg dose in pediatric patients would match exposures determined safe and efficacious in adults; thus, in the phase 1 study, 15 patients, aged 6–11 years and weighing 17–45 kg received a single subcutaneous 75 mg fremanezumab dose. The sparse pharmacokinetic data collected were used to refine the adult model and simulate concentration-time profiles for monthly subcutaneous doses (60 to 225 mg) in a virtual pediatric population.

Results

In the phase 1 pediatric study, the safety profile was similar to that of adults. A two-compartment model with first-order absorption and elimination and body weight effects on clearance and central volume was found to adequately describe the pediatric pharmacokinetic data.

Conclusions

Using exposure matching to the effective adult fremanezumab dose (225 mg subcutaneous monthly), modeling and simulations predict recommended dose of 120 mg in pediatric patients weighing < 45 kg.

Registration: The phase 1 study of this report is registered at EudraCT with the identifier 2018-000734-35.

中文翻译：

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使用来自儿科 1 期研究的药代动力学数据和群体药代动力学建模和模拟方法的 fremanezumab (AJOVY) 3 期儿科偏头痛研究的剂量选择

背景

使用药代动力学模型和模拟评估了儿科患者的潜在 fremanezumab 剂量。在患有偏头痛的儿科患者中进行了一项开放标签的 1 期药代动力学和安全性研究。该研究的结果与成人群体药代动力学模型的改进一起用于确定 fremanezumab 对 3 期儿科研究的剂量建议。

方法

成人模型的初始应用表明，75 毫克剂量的儿童患者将与确定成人安全有效的暴露量相匹配；因此，在 1 期研究中，15 名年龄在 6-11 岁、体重在 17-45 公斤的患者接受了单次皮下注射 75 mg fremanezumab 剂量。收集的稀疏药代动力学数据用于改进成人模型并模拟虚拟儿科人群中每月皮下剂量（60 至 225 毫克）的浓度-时间曲线。

结果

在 1 期儿科研究中，安全性与成人相似。发现具有一级吸收和消除以及体重对清除率和中心容积的影响的二室模型可以充分描述儿科药代动力学数据。

结论

使用与有效成人 fremanezumab 剂量（每月 225 毫克皮下注射）匹配的暴露量，建模和模拟预测体重 < 45 公斤的儿科患者的推荐剂量为 120 毫克。

注册：本报告的第一阶段研究在 EudraCT 注册，标识符为 2018-000734-35。