目的:这项首次人体试验旨在研究健康受试者皮下单次递增剂量聚乙二醇-促红细胞生成素(PEG-EPO)的药代动力学和药效学特征以及安全性和耐受性。
方法:在第一阶段,随机化,双盲,安慰剂对照,剂量递增试验,我们将受试者依次纳入7个队列,每个队列12名受试者,并以5:1的比例随机分组,接受0.2,0.4,0.8,1.6,2.4,3.6或4.8µg/kgPEG-EPO单剂量或匹配安慰剂.评估安全性和耐受性,包括剂量限制性毒性(DLT)。药代动力学参数,包括Cmax,AUC0-inf,Tmax,和t1/2,以及药效学参数,包括网织红细胞计数和血红蛋白含量,进行了评估。
结果:纳入84名受试者(平均年龄30.4岁,77.4%为男性)。没有受试者发生DLT。任何级别治疗相关的不良事件发生在66.7%的受试者中,但大多数(92.9%)为轻度。无严重不良事件发生,无死亡。接受PEG-EPO的受试者中有40%的铁降低,27.1%报告铁蛋白下降,25.7%显示不饱和铁结合能力增加,17.1%中性粒细胞计数下降。Cmax表现出剂量不成比例的上升,从0.2µg/kgPEG-EPO的525pg/mL的几何平均值上升到4.8µg/kgPEG-EPO的23196pg/mL。平均t1/2在使用0.4µg/kgPEG-EPO时介于82.4±21.3h和使用1.6µg/kgPEG-EPO时介于160.6±65.7h之间。AUC0-inf显示出与剂量成比例的上升,从0.2µg/kgPEG-EPO的226264.5pg*h/mL上升到4.8µg/kgPEG-EPO的5206434.0pg*h/mL。绝对网织红细胞计数随着PEG-EPO剂量的增加而增加,PEG-EPO为0.2µg/kg和9.3±4.0*10^10/L(Q1,Q3为1.8-3.6*10^10/L)与3.6µg/kgPEG-EPO的基线平均最大变化范围为3.2±1.5*10^10/L(Q1,Q3为6.2-13.5*10^10/L)。平均血红蛋白含量相对于基线的平均最大变化范围为5.9±4.4g/L(Q1,Q33.5,7.0)与0.2µg/kgPEG-EPO和15.4±8.7g/L(Q1,Q310.5,20.0)与2.4µg/kgPEG-EPO。
结论:该试验证明PEG-EPO在健康受试者中是安全和可耐受的。皮下给药途径允许门诊治疗,PEG-EPO的药代动力学特征支持频率较低的给药方案和对患有贫血的慢性肾病患者的有效治疗。
背景:clinicaltrials.gov标识符:NCT03657238。
OBJECTIVE: This first-in-human trial aimed to investigate the pharmacokinetics and pharmacodynamics characteristics and safety and tolerability of single ascending doses of subcutaneous polyethylene glycol-erythropoietin (PEG-EPO) in healthy subjects.
METHODS: In this phase I, randomized, double-blind, placebo-controlled, dose-escalating trial, subjects were sequentially enrolled into 7 cohorts with 12 subjects in each cohort and randomized in a 5:1 ratio to receive a single dose of 0.2, 0.4, 0.8, 1.6, 2.4, 3.6, or 4.8 µg/kg PEG-EPO or matching placebo. Safety and tolerability including dose-limiting toxicities (DLTs) were assessed. Pharmacokinetics parameters, including Cmax, AUC0-inf, Tmax, and t1/2, and pharmacodynamics parameters, including reticulocyte count and hemoglobin content, were evaluated.
RESULTS: Eighty-four subjects (median age 30.4 years and 77.4% male) were enrolled. No subjects developed DLTs. Any grade treatment-related adverse events occurred in 66.7% of the subjects, but most (92.9%) were mild. No serious adverse events and no death occurred. Forty percent of the subjects receiving PEG-EPO had iron decreased, 27.1% reported ferritin decreased, 25.7% showed unsaturated iron binding capacity increased, and 17.1% had neutrophil count decreased. Cmax exhibited a dose-disproportionate rise from a geometric mean of 525 pg/mL with 0.2 µg/kg PEG-EPO to 23196 pg/mL with 4.8 µg/kg PEG-EPO. The mean t1/2 ranged between 82.4 ± 21.3 h with 0.4 µg/kg PEG-EPO and 160.6 ± 65.7 h with 1.6 µg/kg PEG-EPO. AUC0-inf displayed a largely dose-proportional rise from 226264.5 pg*h/mL with 0.2 µg/kg PEG-EPO to 5206434.0 pg*h/mL with 4.8 µg/kg PEG-EPO. The absolute reticulocyte count increased with escalating doses of PEG-EPO, with the mean maximal change from baseline between 3.2 ± 1.5*10^10/L (Q1,Q3 1.8-3.6*10^10/L) with PEG-EPO 0.2 µg/kg and 9.3 ± 4.0*10^10/L (Q1,Q3 6.2-13.5*10^10/L) with 3.6 µg/kg PEG-EPO. The mean maximal change from baseline in the mean hemoglobin content ranged between 5.9 ± 4.4 g/L (Q1,Q3 3.5,7.0) with 0.2 µg/kg PEG-EPO and 15.4 ± 8.7 g/L (Q1,Q3 10.5,20.0) with 2.4 µg/kg PEG-EPO.
CONCLUSIONS: This trial demonstrated that PEG-EPO was safe and tolerable in healthy subjects. The subcutaneous route of administration allows outpatient treatment and the pharmacokinetics characteristics of PEG-EPO support less frequent dosing regimens and effective treatment for chronic kidney disease patients with anemia.
BACKGROUND: clinicaltrials.gov identifier: NCT03657238.