Department of Pharmacy, Beijing An Ding Hospital, Capital Medical University, No.5 Ankang Hutong, Xicheng District, Beijing, 100088, China.
Phase I Clinical Trial Unit, Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South Road, Chaoyang District, Beijing, 100020, China.
BMC Pharmacol Toxicol. 2024 Jan 2;25(1):6. doi: 10.1186/s40360-023-00729-z.
Definity is an ultrasound contrast agent consisting of phospholipids-encapsulated perfluoropropane (PFP), also known as perflutren, microspheres, which is initially designed to enhance echocardiographic ultrasound images. With no pharmacologic action, Definity can increase the backscatter of ultrasound resulting enhanced ultrasound signals. The objective of this study was to determine the pharmacokinetics (PKs), Pharmacodynamics (PDs) and safety of Definity in healthy male and female Chinese volunteers.
A simple GC-MS method was developed and applied to simultaneously quantify PFP both in human whole blood and in expired air using Perfluorobutane (PFB) as internal standard. Meanwhile, the blood microbubble Doppler intensities were continuously monitored as companion PDs by a Doppler ultrasonography system using a non-imaging method.
After intravenous infusion of 10 µL/kg of PFP within 30 seconds, the mean AUC of the pharmacokinetic analysis set was 0.000653 (uL/mL)*min, the average AUC was 0.001051 (uL/mL)*min. The main coefficient of variation of parameters were within 30%. In this trial, the blood drug concentration of female subjects was lower than that of males. Female C, AUC and AUC were lower than males', T and t was close to males', V and CL were slightly higher than males'. The concentration of PFP in the expired air of the subject reached the maximum value 1-2 min after administration and the PFP accumulation curve in the expired air began to become flat at 9.5-11 min after administration. The PFP in the expired air at the last sampling point of most subjects was still measurable. The results of the analysis showed that female subjects had slightly more and faster PFP excretion via the lungs than males. The change of blood drug concentration in this trial was related to the change process of Doppler signal intensity. The trend of the two was close, but the peak time of blood drug concentration was slightly delayed compared with the peak time of the Doppler signal intensity. The results showed that female t, t was earlier than male, and women have lower AUC than men.
The pharmacokinetics and pharmacodynamics of Definity in blood and expired air were systematically evaluated for the first time in this study. The PK/PD analysis results of this trial showed that the change of blood concentration was related to the change process of Doppler signal intensity, the trend of the two was close and expired air are the main excretion pathways of Definity. Definity was well tolerated by all subjects in the trial.
This study was registered on 08 December 2017 at the Chinese Clinical Trial Registry (CTR20171087).
Definity 是一种由磷脂包裹的全氟丙烷（PFP）组成的超声造影剂，也称为全氟戊烷微球，最初旨在增强超声心动图的超声图像。由于没有药理作用，Definity 可以增加超声的背向散射，从而增强超声信号。本研究的目的是确定 Definity 在健康男性和女性中国志愿者中的药代动力学（PK）、药效学（PD）和安全性。
建立了一种简单的 GC-MS 方法，用于同时定量人全血和呼气中的 PFP，以 Perfluorobutane（PFB）作为内标。同时，使用非成像方法通过多普勒超声系统连续监测血液微泡的多普勒强度作为伴随 PDs。
静脉注射 10 µL/kg PFP 后 30 秒内，药代动力学分析集的平均 AUC 为 0.000653（µL/mL）*min，平均 AUC 为 0.001051（µL/mL）*min。参数的主要变异系数均在 30%以内。在这项试验中，女性受试者的血药浓度低于男性。女性 C、AUC 和 AUC 均低于男性，T 和 t 接近男性，V 和 CL 略高于男性。受试者呼气中 PFP 的浓度在给药后 1-2 分钟达到最大值，给药后 9.5-11 分钟呼气中 PFP 的积累曲线开始变平。大多数受试者最后一个采样点的呼气中 PFP 仍可测量。分析结果表明，女性通过肺部排泄 PFP 的速度略快，排泄量略多。本试验中血药浓度的变化与多普勒信号强度的变化过程有关。两者的趋势相近，但血药浓度的峰值时间略滞后于多普勒信号强度的峰值时间。结果表明，女性 t、t 早于男性，女性 AUC 低于男性。
本研究首次系统评价了 Definity 在血液和呼气中的药代动力学和药效学。本试验的 PK/PD 分析结果表明，血药浓度的变化与多普勒信号强度的变化过程有关，两者的趋势相近，呼气是 Definity 的主要排泄途径。试验中所有受试者均耐受良好。
本研究于 2017 年 12 月 8 日在中国临床试验注册中心（CTR20171087）注册。
