Pharmacokinetics and pharmacodynamics of perfluoropropane after intra-venous bolus injection of perflutren lipid microsphere injection (DEFINITY®) in healthy Chinese volunteers

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 AUClast 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 Cmax, AUClast and AUC∞ were lower than males’, Tmax and t1/2 was close to males’, Vss 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 tmax−pd, t10 was earlier than male, and women have lower AUCpd 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).