Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark.
Drugs R D. 2020 Jun;20(2):75-82. doi: 10.1007/s40268-020-00297-1.
Extended half-life (EHL) factor VIII (FVIII)-replacement therapies enable patients with haemophilia A to maintain higher activity levels with fewer injections. N8-GP (turoctocog alfa pegol; Esperoct) is an EHL product derived from conjugation of polyethylene glycol (PEG) to a recombinant FVIII protein. Upon activation, PEG is released from the active protein and excreted in urine and faeces. While PEG levels are expected to reach steady state with repeated dosing, there has been some discussion regarding whether abnormal accumulation of PEG in plasma and tissues may occur.
Our objective was to examine plasma PEG concentrations in rats and humans repeatedly treated with N8-GP for periods of up to 5 years.
PEG levels were measured using liquid chromatography-tandem mass spectrometry in plasma samples from rats treated with N8-GP as part of a 52-week toxicity study. Human plasma samples from children, adolescents and adults treated with N8-GP as part of the pathfinder programme were also examined (NCT01731600; NCT01480180). These data were compared with steady-state PEG levels predicted by pharmacokinetic modelling of single-dose rat data.
PEG levels reached steady state in plasma in both rats and humans after repeated dosing. The timing and degree of PEG increase to steady state were in line with or below model predictions, confirming the utility of the pharmacokinetic model and indicating that rat data can be used to estimate human plasma PEG levels.
Steady-state PEG levels were reached in plasma from rats and humans repeatedly treated with N8-GP. No unexpected increase in PEG was observed.
延长半衰期（EHL）因子 VIII（FVIII）替代疗法使 A 型血友病患者能够通过更少的注射来维持更高的活动水平。N8-GP（turoctocog alfa pegol； Esperoct）是一种源自聚乙二醇（PEG）与重组 FVIII 蛋白缀合的 EHL 产品。在激活后，PEG 从活性蛋白中释放出来并在尿液和粪便中排泄。虽然随着重复给药，PEG 水平预计会达到稳定状态，但有人讨论过是否会发生 PEG 在血浆和组织中的异常积累。
我们的目的是检查重复接受 N8-GP 治疗长达 5 年的大鼠和人类的血浆 PEG 浓度。
使用液相色谱-串联质谱法测量 N8-GP 治疗大鼠的血浆样本中的 PEG 水平，这是一项为期 52 周的毒性研究的一部分。还检查了接受 N8-GP 治疗的儿童、青少年和成人的人类血浆样本，这些样本来自探索性计划（NCT01731600；NCT01480180）。这些数据与单次剂量大鼠数据的药代动力学模型预测的稳态 PEG 水平进行了比较。
在大鼠和人类中，重复给药后，PEG 水平在血浆中达到稳定状态。PEG 增加到稳定状态的时间和程度与模型预测一致或低于模型预测，证实了药代动力学模型的实用性，并表明可以使用大鼠数据来估计人类血浆 PEG 水平。
重复接受 N8-GP 治疗的大鼠和人类的血浆中达到了稳态 PEG 水平。未观察到 PEG 意外增加。
