Background Intravenous phenobarbital remains the first-line therapy in the management of neonatal seizures. Shortages of intravenous phenobarbital in South Africa necessitated the addition of oral levetiracetam as part of management of neonatal seizures. Objective We evaluated the pharmacokinetics of crushed immediate-release levetiracetam tablets administered to neonates to terminate seizures. Methods A prospective, observational study of neonates admitted with seizures to Tygerberg Hospital. Participants received crushed levetiracetam (diluted in saline) given orally or via naso-/orogastric tube. At steady-state, pharmacokinetic sampling was performed at pre-dose, 1.5, 2.5 and 4 h post-dose. Maximum concentration (Cmax), time to Cmax (Tmax), trough concentrations (Ctrough) and area under the concentration-time curve (AUC0–12) were calculated using non-compartmental analysis. Seizure termination and safety profiles were documented. Results Nineteen participants were grouped into three dosing ranges: (i) 5–15 mg/kg/12-hourly, (ii) 15–25 mg/kg/12-hourly and (iii) 25–35 mg/kg/12-hourly. Range 1 demonstrated AUC0–12 167.0 ± 45.6 h*μg/mL, Cmax 19.19 ± 4.12 μg/mL and Ctrough 9.99 ± 3.86 µg/mL. Range 2, AUC0–12 316.5 ± 108.4 h*μg/mL, Cmax 35.12 ± 10.54 µg/mL and Ctrough 19.25 ± 8.48 µg/mL. Range 3, AUC0–12 290.9 (range 176.14–405.59) h*μg/mL, Cmax 36.11 (range 27.58–44.64) µg/mL and Ctrough 13.03 (2.98–23.07) µg/mL. Seizures terminated in 17/19 (90%) neonates by day 3 and 19/19 (100%) by day 4 post-levetiracetam initiation. Conclusion Crushed levetiracetam has comparable pharmacokinetics to historical data. No pharmacokinetic differences were observed between oral vs. naso-/orogastric administration. Crushed levetiracetam tablets can be considered for neonates in low-resource settings where intravenous and syrup access is limited. LAY SUMMARY Intravenous preparations of antiepileptic medications are used in the management of neonatal seizures. Various established standard of care intravenous antiepileptic medicines are unavailable nationally and internationally due to reasons outside our control. This stock shortage included intravenous phenobarbitone which is the first-line treatment for paediatric seizures. Due to phenobarbital shortage, levetiracetam has been identified by the neonatologists at Tygerberg Hospital, Cape Town, South Africa, as a suitable treatment option due to its efficacy and safety profile. However, intravenous levetiracetam and oral syrup is not registered in South Africa. Levetiracetam tablets are being crushed, dissolved and administered to neonates. There are no data available on the absorption of crushed levetiracetam tablets administered to neonates via a nasogastric tube. This study characterized the pharmacokinetic profile of crushed levetiracetam administered to neonates. We selected neonates receiving levetiracetam from the neonatal wards at Tygerberg hospital and drew blood to analyse the levetiracetam concentrations at 4 different time points. We found that the overall exposure of crushed levetiracetam tablets were comparable to the exposures achieved in historical data of the unaltered formulations. We concluded that crushed levetiracetam tablets can be considered for neonates in low resource settings where intravenous and syrup access is limited.

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新生儿左乙拉西坦粉碎片的药代动力学

背景 静脉内苯巴比妥仍然是新生儿癫痫发作的一线治疗。南非静脉注射苯巴比妥的短缺需要增加口服左乙拉西坦作为新生儿癫痫发作管理的一部分。目的我们评价了压碎的速释左乙拉西坦片用于新生儿终止癫痫发作的药代动力学。方法 对 Tygerberg 医院因癫痫发作而入院的新生儿进行的一项前瞻性观察性研究。参与者口服或通过鼻/口胃管接受压碎的左乙拉西坦（用盐水稀释）。在稳态下，在给药前、给药后 1.5、2.5 和 4 小时进行药代动力学采样。最大浓度 (Cmax)，达到 Cmax 的时间 (Tmax)，谷浓度 (Ctrough) 和浓度 - 时间曲线下面积 (AUC0-12) 使用非房室分析计算。记录了癫痫发作终止和安全概况。结果 19 名参与者被分为三个剂量范围：(i) 5–15 mg/kg/12 小时，(ii) 15–25 mg/kg/12 小时和 (iii) 25–35 mg/kg/12-每小时。范围 1 显示 AUC0–12 167.0 ± 45.6 h*μg/mL，Cmax 19.19 ± 4.12 μg/mL 和 Ctrough 9.99 ± 3.86 μg/mL。范围 2，AUC0–12 316.5 ± 108.4 h*μg/mL，Cmax 35.12 ± 10.54 µg/mL 和 Ctrough 19.25 ± 8.48 µg/mL。范围 3，AUC0–12 290.9（范围 176.14–405.59）h*μg/mL，Cmax 36.11（范围 27.58–44.64）µg/mL 和 Ctrough 13.03 (2.98–23.07) µg/mL。17/19 (90%) 新生儿在左乙拉西坦开始后第 3 天和 19/19 (100%) 终止癫痫发作。结论 压碎的左乙拉西坦具有与历史数据相当的药代动力学。口服与经鼻/口胃给药之间未观察到药代动力学差异。在资源匮乏地区，静脉注射和糖浆通路受限的新生儿可考虑粉碎左乙拉西坦片剂。LAY Summary 抗癫痫药物的静脉制剂用于新生儿癫痫发作的治疗。由于我们无法控制的原因，各种既定标准的静脉内抗癫痫药物在国内和国际上都无法使用。这种库存短缺包括静脉注射苯巴比妥，这是儿科癫痫发作的一线治疗药物。由于苯巴比妥短缺，左乙拉西坦已被南非开普敦泰格伯格医院的新生儿科医生鉴定，由于其疗效和安全性，作为一种合适的治疗选择。然而，静脉注射左乙拉西坦和口服糖浆未在南非注册。左乙拉西坦片剂正在被压碎、溶解并给予新生儿。没有关于通过鼻胃管给予新生儿压碎的左乙拉西坦片剂吸收的数据。该研究描述了给予新生儿的压碎左乙拉西坦的药代动力学特征。我们从 Tygerberg 医院的新生儿病房选择接受左乙拉西坦的新生儿，并抽血分析 4 个不同时间点的左乙拉西坦浓度。我们发现，压碎的左乙拉西坦片剂的总暴露量与未改变配方的历史数据中的暴露量相当。