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首页> 美国卫生研究院文献>Clinical and Translational Science >Clinical Pharmacokinetics and Pharmacodynamics of Cerliponase Alfa Enzyme Replacement Therapy for CLN2 Disease by Intracerebroventricular Administration
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Clinical Pharmacokinetics and Pharmacodynamics of Cerliponase Alfa Enzyme Replacement Therapy for CLN2 Disease by Intracerebroventricular Administration

机译：Cerliponase Alfa的临床药代动力学和药效学Intracebrinallary施用Crn2疾病酶替代疗法

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Cerliponase alfa is recombinant human tripeptidyl peptidase 1 (TPP1) delivered by i.c.v. infusion for CLN2, a pediatric neurodegenerative disease caused by deficiency in lysosomal enzyme TPP1. We report the pharmacokinetics (PK) and pharmacodynamics of cerliponase alfa, the first i.c.v. enzyme replacement therapy, characterized in a phase I/II study. Escalating doses (30–300 mg Q2W) followed by 300 mg Q2W for ≥ 48 weeks were administered in 24 patients aged ≥ 3 years. Concentrations peaked in cerebrospinal fluid (CSF) at the end of ~ 4‐hour i.c.v. infusion and 8 hours thereafter in plasma. Plasma exposure was 300–1,000‐fold lower than in CSF, with no correlation in the magnitude of peak concentration (Cmax) or area under the concentration‐time curve (AUC) among body sites. There was no apparent accumulation in CSF or plasma exposure with Q2W dosing. Interpatient and intrapatient variability of AUC, respectively, were 31–49% and 24% in CSF vs. 59–103% and 80% in plasma. PK variability was not explained by baseline demographics, as sex, age, weight, and CLN2 disease severity score did not appear to impact CSF or plasma PK. No apparent correlation was noted between CSF or plasma PK and incidence of adverse events (pyrexia, hypersensitivity, seizure, and epilepsy) or presence of antidrug antibodies in CSF and serum. There was no relationship between magnitude of CSF exposure and efficacy (change in CLN2 score from baseline), indicating maximum benefit was obtained across the range of exposures with 300 mg Q2W. Data from this small trial of ultra‐rare disease were leveraged to adequately profile cerliponase alfa and support 300 mg i.c.v. Q2W for CLN2 treatment.
机译：Cerliponase Alfa是由I.C.V递送的重组人三肽基肽酶1（TPP1）。对ClN2的输注，一种由溶酶体酶TPP1缺乏引起的小儿神经退行性疾病。我们报告了Cerliponase Alfa的药代动力学（PK）和药效学，第一个I.C.V。酶替代疗法，其特征在于I / II期研究。升级剂量（30-300mg Q2W）随后在24岁≥3岁的患者中施用300mg Q2W≥48周。在〜4小时I.C.V的末端，浓度达到脑脊液（CSF）。输液和在等离子体中的8小时。血浆暴露于CSF中的血浆暴露300-1,000倍，在浓度 - 时间曲线（AUC）下的峰浓度（CMAX）或面积中没有相关性，在身体部位之间的浓度浓度（CMAX）或面积。 CSF中没有明显的积累或Q2W给药的血浆暴露。 AUC的介入性和对腔内可变性分别为31-49％，在血浆中的CSF与59-103％和80％的24％。基线人口统计学没有解释PK变异性，作为性别，年龄，体重和CLN2疾病严重程度得分没有影响CSF或血浆PK。在CSF或血浆PK和不良事件（Pyrexia，超敏反应，癫痫发作和癫痫发作）之间没有明显相关性，或在CSF和血清中存在抗胚抗体。 CSF暴露和功效的幅度之间没有关系（从基线的CLN2评分的变化），在300mg Q2W的曝光范围内获得最大效益。来自这种小型试验的超罕见疾病的数据被利用，以充分剖到Cerliponase Alfa并支持300mg I.C.V。 Q2W用于CLN2处理。

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