Peters Esther, Heuberger Jules A A C, Tiessen Renger, van Elsas Andrea, Masereeuw Rosalinde, Arend Jacques, Stevens Jasper, Pickkers Peter
Department of Intensive Care Medicine, Radboud university medical center, PO Box 9101, Internal Mailbox, 710, 6500 HB, Nijmegen, The Netherlands.
Department of Pharmacology and Toxicology, Radboud university medical center, Nijmegen, The Netherlands.
Clin Pharmacokinet. 2016 Oct;55(10):1227-1237. doi: 10.1007/s40262-016-0399-y.
Previous clinical trials have suggested that bovine intestinal alkaline phosphatase has renal protective effects in patients with sepsis-associated acute kidney injury. We conducted a first-in-human study to investigate the pharmacokinetics, safety and tolerability of a novel human recombinant alkaline phosphatase (recAP), and we developed a population pharmacokinetic model to support dose selection for future patient studies.
In a randomized, double-blind, placebo-controlled, phase I trial, healthy volunteers received a single dose of recAP (200, 500, 1000 or 2000 U/kg; n = 33; 3:1 ratio) or multiple doses of recAP (500 or 1000 U/kg; n = 18; 2:1 ratio) via a 1-h intravenous infusion on three consecutive days. Serum recAP concentrations, alkaline phosphatase (AP) activity levels and anti-drug antibodies were measured, and safety parameters were monitored. A population pharmacokinetic model was developed, and simulations were performed to guide dose selection for a phase IIa/b trial.
Peak concentrations of recAP and peak AP activity were reached at the end of the 1-h infusion and showed a rapid decline, with about 10 % of the maximum concentration remaining at 4 h and less than 5 % remaining 24 h post-start. RecAP treatment was generally well tolerated, and anti-drug antibodies could not be detected in the serum up to 2 weeks post-injection after a single dose, or up to 3 weeks post-injection after multiple doses. A four-compartment model best described the pharmacokinetics of recAP administration, with moderate inter-individual variability on the central volume of distribution and elimination rate constant. Simulations showed that 1-h intravenous infusions of 250, 500 and 1000 U/kg recAP once every 24 h for three consecutive days constituted the dosing regimen that best met the criteria for dose selection in patient studies.
RecAP did not raise any safety concerns when administered to healthy volunteers. A population pharmacokinetic model was developed to support dose selection for patient studies.
2013-002694-21 (EudraCT).
既往临床试验表明，牛小肠碱性磷酸酶对脓毒症相关性急性肾损伤患者具有肾脏保护作用。我们开展了一项人体首次研究，以调查新型人重组碱性磷酸酶（recAP）的药代动力学、安全性及耐受性，并建立了群体药代动力学模型，以支持未来患者研究的剂量选择。
在一项随机、双盲、安慰剂对照的I期试验中，健康志愿者连续3天通过1小时静脉输注接受单剂量recAP（200、500、1000或2000 U/kg；n = 33；3:1比例）或多剂量recAP（500或1000 U/kg；n = 18；2:1比例）。检测血清recAP浓度、碱性磷酸酶（AP）活性水平及抗药抗体，并监测安全性参数。建立了群体药代动力学模型，并进行模拟以指导IIa/b期试验的剂量选择。
recAP的峰值浓度及AP活性峰值在1小时输注结束时达到，并迅速下降，开始后4小时约有10%的最大浓度留存，24小时后留存不足5%。recAP治疗总体耐受性良好，单剂量注射后2周内或多剂量注射后3周内血清中均未检测到抗药抗体。一个四室模型能最好地描述recAP给药的药代动力学，中央分布容积和消除速率常数存在中度个体间变异性。模拟显示，连续3天每天1次、每次24小时静脉输注250、500和1000 U/kg recAP构成了最符合患者研究剂量选择标准的给药方案。
recAP应用于健康志愿者时未引发任何安全问题。建立了群体药代动力学模型以支持患者研究的剂量选择。
2013-002694-21（欧盟临床试验数据库）
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