Pharmacokinetics, Dialysability, and Safety of Gadopiclenol, a New Gadolinium-Based Contrast Agent, in Patients With Impaired Renal Function
Pharmacokinetics, Dialysability, and Safety of Gadopiclenol, a New Gadolinium-Based Contrast Agent, in Patients With Impaired Renal Function
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DOI：
10.1097/rli.0000000000000764
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发表时间：
2021-08-01
影响因子：
6.7
通讯作者：
Bourrinet, Philippe
中科院分区：
文献类型：
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作者：
Bradu, Andrei;Penescu, Mircea;Bourrinet, Philippe
目的本研究的目的是评价一种新的大环钆基造影剂gadopiclenol在肾功能受损受试者中的药代动力学（PK），并评估其在终末期肾病（ESRD）受试者中的透析能力。方法和材料这项2中心、开放标签、I期研究包括5个连续队列的8例成人受试者：健康受试者（队列1）、轻度（队列2）、中度（队列3）、重度（队列4）肾损害或ESRD（队列5）受试者，接受单次静脉注射gadopiclenol（0. 1 mmol/kg）。在队列1至4的不同时间点采集血液和尿液样本，在队列5的每次血液透析治疗（第1、3和5天的4小时治疗）时采集血液和透析液样本。对Gadopiclenol的消除和安全性进行了长达6个月的评估。使用非房室分析计算药代动力学参数。结果共纳入40例受试者，年龄18-71岁，平均51.5岁。在队列1至队列4中未观察到平均最大浓度值和分布容积的显著差异。原型gadopiclenol的尿排泄随肾损害程度而延迟，轻度至重度肾损害受试者的排泄率范围为96%至84%。与健康受试者相比，轻度、中度和重度肾损害受试者的平均血药浓度曲线下面积分别高54%、148%和769%。平均终末半衰期随肾损害程度延长（队列1-4为1.9、3.3、3.8和11.7小时）。在ESRD受试者中，首次血液透析后，Gadopiclenol从血浆中有效清除（95%-98%）。第二次血液透析后，所有受试者的血浆中Gadopiclenol浓度均低于定量限。在1、3和6个月时采集的所有血浆和尿液样本中，Gadopiclenol浓度均低于定量限。5例受试者（12.5%）发生了与gadopiclenol相关的不良事件，无严重事件，均已消退。实验室测量、生命体征和心电图未引起任何安全性问题。结论Gadopiclenol在轻度至重度肾损害患者中的消除半衰期延长，但其肾脏清除仍保持完全或接近完全。在ESRD受试者中，1次血液透析后，Gadopiclenol从血浆中有效清除，最多3次血液透析足以完全清除，未出现安全性问题。因此，在该患者人群中似乎无需调整剂量。
Objectives The aims of this study were to evaluate the pharmacokinetics (PK) of gadopiclenol, a new macrocyclic gadolinium based-contrast agent, in subjects with impaired renal function, and to assess its dialysability in subjects with end-stage renal disease (ESRD). Methods and Materials This 2-center, open-label, phase 1 study included 5 successive cohorts of 8 adult subjects: healthy subjects (cohort 1), subjects with mild (cohort 2), moderate (cohort 3), severe (cohort 4) renal impairment, or ESRD (cohort 5), who received a single intravenous injection of gadopiclenol (0.1 mmol/kg). Blood and urine samples were collected at different time points in cohorts 1 to 4, and blood and dialysate samples were collected at each hemodialysis session (4-hour session on day 1, day 3, and day 5) in cohort 5. Gadopiclenol elimination and safety were assessed for up to 6 months. Pharmacokinetics parameters were calculated using noncompartmental analysis. Results A total of 40 subjects were included, with a mean age of 51.5 years (range, 18-71 years). No significant difference in the mean maximum concentration values and the distribution volume was observed among cohorts 1 to 4. Urinary excretion of unchanged gadopiclenol was delayed with the degree of renal impairment and ranged between 96% and 84% in subjects with mild to severe renal impairment. Compared with that of healthy subjects, the mean area under the plasma concentration curve was 54%, 148%, and 769% higher in subjects with mild, moderate, or severe renal impairment, respectively. The mean terminal half-life was prolonged with the degree of renal impairment (1.9, 3.3, 3.8, and 11.7 hours for cohorts 1-4). In ESRD subjects, gadopiclenol was effectively removed from the plasma (95% to 98%) after the first hemodialysis session. Gadopiclenol concentration in plasma was below the limit of quantification for all subjects after the second hemodialysis session. Gadopiclenol concentration was below limit of quantification in all plasma and urine samples collected at 1, 3, and 6 months. Five subjects (12.5%) experienced adverse events related to gadopiclenol, none serious and all resolved. Laboratory measurements, vital signs, and electrocardiography did not raise any safety concern. Conclusions Gadopiclenol elimination half-life was prolonged in subjects with mild to severe renal impairment, yet its renal clearance remains complete or nearly complete. In ESRD subjects, gadopiclenol was effectively removed from the plasma after 1 hemodialysis session, and up to 3 hemodialysis sessions were sufficient to completely clear it. No safety concern was raised. Therefore, no dose adjustment seems necessary in this patient population.