Chanu Pascal, Schaefer Franz, Warady Bradley A, Schmitt Claus Peter, Reigner Bruno, Schnetzler Gabriel, Meyer Reigner Sylvie, Eisner Mark, Weichert Arlette, Frey Nicolas
Clinical Pharmacology, Genentech/Roche, Lyon, France.
University of Heidelberg, Heidelberg, Germany.
Br J Clin Pharmacol. 2020 Apr;86(4):801-811. doi: 10.1111/bcp.14186. Epub 2020 Jan 21.
Methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator, C.E.R.A.) is used for the treatment of anaemia in adults with chronic kidney disease (CKD). Patients treated with shorter-acting erythropoiesis-stimulating agents up to three times weekly can be switched to once-monthly C.E.R.A.. Doses can be adjusted on a monthly basis based on haemoglobin (Hb) levels during the preceding period. A model-based approach was applied to optimise C.E.R.A. development, more specifically the confirmatory trial of the paediatric plan.
Pharmacokinetic and pharmacodynamic data from a phase II paediatric study and phase II and III adult studies were analysed together using modelling and simulation to determine the pharmacokinetic/pharmacodynamic characteristics of C.E.R.A. in a broad population. Model-based simulations of C.E.R.A. treatment outcomes in paediatric patients were performed, notably when administered subcutaneously and compared to clinical and real-world data.
Age and body weight explained differences in pharmacokinetics, while the pharmacodynamic characteristics of C.E.R.A. were similar between adult and paediatric populations. Simulated Hb levels (mean and 95% prediction interval 10.9 [10.6, 11.2] g dL ) and C.E.R.A. doses (median and 95% prediction interval 105 [72, 159] μg) 20 weeks after switching to subcutaneous C.E.R.A. were confirmed by observed real-world data from International Pediatric Dialysis Network registries (mean Hb was 10.8 g dL and median C.E.R.A. dose was 100 μg).
These analyses have facilitated optimisation of the C.E.R.A. development programme in paediatric patients with anaemia of CKD to provide this patient population with faster access to the drug while avoiding unnecessary clinical trial exposure and related monitoring burden in children.
甲氧基聚乙二醇 - 促红细胞生成素β（持续促红细胞生成素受体激活剂，C.E.R.A.）用于治疗成年慢性肾脏病（CKD）患者的贫血。接受短效促红细胞生成刺激剂治疗、每周最多三次的患者可改用每月一次的C.E.R.A.。剂量可根据前一时期的血红蛋白（Hb）水平每月调整一次。采用基于模型的方法来优化C.E.R.A.的研发，更具体地说是儿科计划的验证性试验。
使用建模和模拟方法共同分析来自一项儿科II期研究以及成人II期和III期研究的药代动力学和药效学数据，以确定C.E.R.A.在广泛人群中的药代动力学/药效学特征。对儿科患者C.E.R.A.治疗结果进行基于模型的模拟，特别是皮下给药时，并与临床和实际数据进行比较。
年龄和体重解释了药代动力学的差异，而C.E.R.A.的药效学特征在成人和儿科人群中相似。转换为皮下注射C.E.R.A. 20周后的模拟Hb水平（均值和95%预测区间为10.9 [10.6, 11.2] g/dL）和C.E.R.A.剂量（中位数和95%预测区间为105 [72, 159] μg）通过国际儿科透析网络登记处的实际观察数据得到证实（平均Hb为10.8 g/dL，C.E.R.A.剂量中位数为100 μg）。
这些分析有助于优化CKD贫血儿科患者的C.E.R.A.研发计划，为该患者群体更快地提供药物，同时避免儿童不必要的临床试验暴露和相关监测负担。
