Pharmacokinetics of Perfluorobutane after Intra-Venous Bolus Injection of Sonazoid in Healthy Chinese Volunteers

Abstract

Sonazoid is an ultrasound contrast agent based on microbubbles (MB) containing perfluorobutane (PFB) gas. Sonazoid is approved in Japan, Korea and Norway for contrast-enhanced ultrasonography of focal liver lesions and focal breast lesions (Japan only). The objective of this study was to determine the pharmacokinetics (PKs) and safety of Sonazoid in Chinese healthy volunteers (HVs) and to evaluate the potential for ethnic differences in PKs between Chinese and Caucasian HVs. Sonazoid was administered as an intra-venous bolus injection at the clinical dose of 0.12 μL or 0.60 μL MB/kg body weight to two groups of eight Chinese HVs. Expired air and blood samples were collected and analyzed using a validated gas chromatographic tandem mass spectrometry method, and the main PK parameters were calculated. The highest PFB concentrations in blood were observed shortly after intra-venous administration of Sonazoid, and elimination of PFB was rapid. In the 0.12 μL MB/kg body weight cohort, PFB concentrations above the limit of quantification were observed for only 10 to 15 min post-injection. In the 0.60 μL MB/kg body weight cohort, PFB concentrations above the limit of quantification were observed for 60 min post-injection, and the shape of the elimination curve suggested a biphasic elimination profile. The maximum observed concentration (C) values of PFB in blood were 2.3 ± 1.1 and 19.1 ± 9.2 ng/g for the 0.12 and 0.60 μL MB/kg body weight dose groups (mean ± standard deviation). Area under the curve values were 10.1 ± 2.7 and 90.1 ± 38.3 ng × min/g for the 0.12 and 0.60 μL MB/kg body weight dose groups. C values of PFB in exhaled air were 0.35 ± 0.2 and 2.4 ± 0.7 ng/mL for the 0.12 and 0.60 μL MB/kg body weight dose groups. Assessment of laboratory parameters, vital signs, oxygen saturation and electrocardiograms revealed no changes indicative of a concern. The PK profile and safety data generated in the Chinese HVs were comparable to previous data for Caucasian HVs.

Contrast Agents for Hepatocellular Carcinoma Imaging: Value and Progression

“…As early as 1 min after the intravenous administration, the MBs start to diffuse into extravascular and intercellular space where they will be phagocytosed by the Kupffer cells in the normal liver sinusoids. Approximately 10 min later, once intravascular MBs are mostly eliminated, the remaining stable MBs endocytosed by resident macrophages in liver parenchyma will shape the so-called additional Kupffer phase or post-vascular phase, which can last to 2 h after injection ( 30 – 32 ) ( Table 1 ). Moreover, in the classical enhancement features of wash-in and wash-out, HCC theoretically appears to be perfusion defects in the Kupffer phase or post-vascular phase because of Kupffer cell shortage ( Figures 1 , 2 ).…”

Microbubble Agents: New Directions

“…Pharmacokinetics and bioavailability for microbubble studies are also performed within a GLP environment, using validated bioanalytical procedures (US Food and Drug Administration 2018; European Medicines Agency 2011). The blood kinetic and elimination of the gas can be accomplished by gas monitoring in blood and exhaled air analysis, using highly sensitive gas chromatography mass spectrometry methods (Schneider et al 2011;Li et al 2017). In parallel, by radiolabeling key moieties of the microbubbles (e.g., phospholipid), a mass balance can be achieved through the collection and testing of blood, urine and fecal samples.…”

Three Decades of Ultrasound Contrast Agents: A Review of the Past, Present and Future Improvements

“…The pharmacokinetics and clinical assessment of Sonazoid showed a very good tolerance of the recommended clinical dose of 0.12 mL perfluorobutane microbubbles/kg weight in healthy adults (Li et al 2017). Low MI (around 0.2 depending on the scanners) together with contrast-specific non-linear imaging methods should be used to avoid microbubble destruction.…”