Paediatric Neurology, Starship Children's Health, Auckland, New Zealand
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
Arch Dis Child. 2024 Sep 25;109(10):854-860. doi: 10.1136/archdischild-2022-324952.
To confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.
Pharmacokinetic data from the NEOLEV1 and NEOLEV2 trials were analysed using a non-linear mixed effects modelling approach. A post hoc analysis of the effect of LEV on seizure burden was conducted.
Neonatal intensive care unit.
Term neonates with electrographically confirmed seizures.
In NEOLEV1, neonates with seizures persisting following phenobarbital (PHB) received LEV 20 or 40 mg/kg bolus followed by 5 or 10 mg/kg maintenance dose(MD) daily. In NEOLEV2, patients received a 40 mg/kg intravenous LEV load, followed by 10 mg/kg doses 8 hourly. If seizures persisted, a further 20 mg/kg intravenous load was given. If seizures persisted, PHB was given. PK data were collected from 16 NEOLEV1 patients and 33 NEOLEV2 patients. cEEG data from 48 NEOLEV2 patients were analysed to investigate onset of action and seizure burden reduction.
Clearance (CL) and volume of distribution (V) were determined. Covariates that significantly affected LEV disposition were identified.
Primary outcome: The median initial LEV level was 57 µg/mL (range 19-107) after the first loading dose and at least 12 µg/mL at 48 hours in all infants. CL and V were estimated to be 0.0538 L/hour and 0.832 L, respectively. A direct relationship between postnatal age and CL was observed. The final population pharmacokinetic(PopPK) model described the observed data well without significant biases. CL and V were described as CL (L/hour)=0.0538×(weight in kg/3.34)0.75×(postnatal age in days/5.5) 0.402 and V (L)=0.832×(weight in kg/3.34).Seizure burden reduced within 30 min of LEV administration. 28% of patients were completely seizure free after LEV. In an additional 25% of patients, seizure burden reduced by 50%.
LEV pharmacokinetics remained predictable at higher doses. Very high-dose LEV can now be studied in neonates.
NCT01720667.
确认左乙拉西坦（LEV）在较高剂量下具有可预测的药代动力学（PK）特性，并研究 LEV 的药效动力学（PD）。
使用非线性混合效应模型分析 NEOLEV1 和 NEOLEV2 试验的药代动力学数据。对 LEV 对癫痫发作负担的影响进行了事后分析。
新生儿重症监护病房。
电描记法证实有癫痫发作的足月新生儿。
在 NEOLEV1 中，接受苯巴比妥（PHB）治疗后仍有癫痫发作的新生儿接受 20 或 40mg/kg 的 LEV 推注，然后每天给予 5 或 10mg/kg 的维持剂量（MD）。在 NEOLEV2 中，患者接受 40mg/kg 的静脉 LEV 负荷量，然后每 8 小时给予 10mg/kg 剂量。如果癫痫发作持续，给予额外的 20mg/kg 静脉负荷量。如果癫痫发作持续，给予 PHB。从 16 名 NEOLEV1 患者和 33 名 NEOLEV2 患者中收集 PK 数据。对 48 名 NEOLEV2 患者的 cEEG 数据进行分析，以研究作用的开始和癫痫发作负担的减轻。
确定清除率（CL）和分布容积（V）。确定对 LEV 处置有显著影响的协变量。
主要结局：所有婴儿首次负荷剂量后初始 LEV 水平中位数为 57μg/mL（范围 19-107），至少在 48 小时时为 12μg/mL。CL 和 V 估计分别为 0.0538L/小时和 0.832L。观察到胎龄与 CL 之间存在直接关系。最终的群体药代动力学（PopPK）模型很好地描述了观察到的数据，没有显著的偏差。CL 和 V 描述为 CL（L/小时）=0.0538×（体重[kg]/3.34）0.75×（胎龄[天]/5.5）0.402，V（L）=0.832×（体重[kg]/3.34）。癫痫发作负担在 LEV 给药后 30 分钟内减轻。LEV 后 28%的患者完全无癫痫发作。在另外 25%的患者中，癫痫发作负担减少了 50%。
LEV 的药代动力学在较高剂量下仍具有可预测性。现在可以在新生儿中研究超高剂量 LEV。
NCT01720667。
