Study On The Pharmacokinetics Of Octafluoropropane-Containing Albumin Microbubbles And Evaluations Of Safety And Tolerability

OBJECTIVES: To assess the exhaled elimination kinetics of Octafluoropropane in anesthetized canines following intravenous administration of octafluoropropane-containing albumin microbubbles and to study the safety and tolerability on healthy volunteers. METHODS: 1. Octafluoropropane-containing albumin microbubbles at dosages of 0.4, 0.8 and 1.2ml/kg were administered intravenously to anesthetized and ventilated canines. The exhaled air samples were analyzed by gas chromatography-MS(GC-MS). 2. The study on the safety and tolerability of the new ultrasound contrast agent was a single-center, single administration, escalating-dose study in five groups of six subjects. Dose of 0.005, 0.01, 0.02, 0.03 and 0.04ml/kg were tested. Subject safety was evaluated through the monitering and assessment of changes in vital signs of physical examination, oxygen saturation, clinical laboratory tests( hematology blood chemistry, arinalysis,etc), 12-lead electro-cardiograms(ECGs) and recording of adverse clinical events(ACEs). RESULTS: 1. The calibration curve of GC-MS was linear within the concentration range of l-400ppm, r=0.9999. The limit of detection was 0.5ppm, and the recovery was 100. 98 + 1. 4%, 102.63 + 2.29%and 97.5 + 2.2% respectively; the RSDs of within-day and between-day were 0.6%-2.0% and 0.86-2.3% respectively. 2. WINNOLIN software and noncompartmental analyses were performed to generate kinetics parameters. In dose of 0.4ml/kg, 0.8ml/kg and 1.2ml/kg, Cmaxwere 2.837 + 0.25, 3.06+0.29 and 13.64+2.99nmol/ml respectively; Tmax were 16. 67+10.53, 21.66+14.12, and 10 + 0.00s respectively. AUC were 154.19 + 61.83, 353.77+77.89 803.21 +335.77nmol.sec/ml respectively; MRT were 98.64+43.01, 137.44+40.86 and 86.96+1.56s respectively; 3. The curve of colleration between AUC and dose was y=1162.5x-417.38 R2=0.9499. 4. Adverse clinical events were reported by three subjects.Two subjects were headache 8hs after 0.005ml/kg dose and one subject was light headed llhs after 0.02ml/kg dose. But no ACEs were considered by the investigators to be possibly related to the study drug. 5. All doses in the study were well tolerated. No treament-related changes in vital signs, ECGs, oxygen saturation, physical examinations, or clinical laboratory tests were observed. CONCLUSIONS: 1. The route of octafluoropropane-containing albumin microbubbles elimination was by means of the lungs in canines in the expired air. The compound were not metabolized. 2. The method of GC-MS is accurate , sensitive, precise and usable for OFP. 3. Octafluoropropane -containing albumin microbubbles was safe and well tolerated at the doses evaluated in the study.