Nonclinical Safety Assessment of Intravenous Optison®: A Perfluoropropane (PFP)-Filled Albumin Microspheres Contrast Agent for Ultrasonography

Abstract

OPTISON (FS069), an ultrasonic diagnostic contrast agent, is a suspension of perfluoropropane (PFP)-filled album in microspheres of 2.0-4.5 microns average diameter and 5.0-8.O x 108 microspheresl ml. The following non clinical safety assessment studies in support of product regulatory submissions were conducted: genetic toxicology, single dose (rat, dog, monkey) and repeated (rat, dog) dose toxicology studies, hemodynamics, rabbit irritation, and in vitro blood compatibility. Dosages used throughout the studies were: 0.25, 5.0, 10, 20, or 25 ml/kg. OPTISON was nongenotoxic and nonirritant, and was compatible with human blood. It did not elicit adverse effects in single-dose studies at dosages of up to (and including) 20 ml/ kg. Initial studies conducted in rats and dogs with OPTISON repeated administration, 3 times per week for 3 weeks, showed no adverse effects in dogs to 20 ml/ kg and rats to 5 ml/kg. Mortality and adverse effects were noted in rats at dosages of 20 and 10 ml/ kg and were associated with acute pulmonary congestion. Subsequent repeated administrations for 29 and 31 consecutive days in rats and dogs, respectively, at 10 ml/kg, were not associated with adverse events, except for those which resulted from the anticipated immunogenic response to the IV administration of OPTISON human albumin-based microspheres. No changes in hemodynamic parameters attributable to OPTISON were reported at a dosage of 0.25 ml/ kg in dogs. It is, therefore, concluded that the intravenous administration of OPTISON, at dosages and dose regimens used in these studies, provides a large safety margin for the clinical efficacious dose for diagnostic ultrasound imaging.

Preclinical Acute Toxicology Study of Surfactant-Stabilized Ultrasound Contrast Agents in Adult Rats

“…The depth scale on the left of each image is in centimeters. 38 This is a very similar result to our study, where 1 and 4 animals died (for ST68 and ST44, respectively) and a statistically significant suspected foreign body reaction was observed in the lungs following injection of either contrast agent (P < .01). It is conceivable that more effects could have been induced in our study by the addition of ultrasound pressure waves (ie, by imaging the animals with ultrasound).…”

“…At the highest dose administered (ie, 25 mL/kg) 3 animals died following breathing problems. 38 This is a very similar result to our study, where 1 and 4 animals died (for ST68 and ST44, respectively) and a statistically significant suspected foreign body reaction was observed in the lungs following injection of either contrast agent ( P < .01).…”

“…An extensive toxicology study of a commercial ultrasound contrast agent (Optison; GE Healthcare, Princeton, NJ) was performed by Greener and coworkers. 38 They reported on genetic toxicology as well as single-dose and repeated-dose toxicology studies performed in rats, dogs, and monkeys for dosages of 0.25, 5.0, 10, 20, and 25 mL/kg (0.25 mL/kg is the highest possible clinical dose). Compared with controls, there were no adverse effects in the acute, single-dose rat studies (N = 46) at dosages of 0.25, 5.0, and 20 mL/kg.…”

“…36,37 An extensive toxicology study of a commercial ultrasound contrast agent (Optison; GE Healthcare, Princeton, NJ) was performed by Greener and coworkers. 38 They reported on genetic toxicology as well as single-dose and repeated-dose toxicology studies performed in rats, dogs, and monkeys for Rat kidneys (arrows) imaged in power Doppler imaging (PDI) mode (the green box delineates the region within which blood flow is measured) before injection of ST44 and ST68 (a and f, respectively) and following injection (b-e and g-j, respectively). Dosages are 0.1, 0.2, 0.8, and 1.0 mL/kg from left to right (ie, b-e and g-j).…”

Use of Contrast‐Enhanced Sonography to Investigate Intraneural Vascularity in a Cohort of Macaca fascicularis With Suspected Median Mononeuropathy

“…This dose was well below amounts indicated in toxicology reports of sonographic contrast agent injections in monkeys. 16,17 During the working phase, all subjects were intubated during contrast agent injections for fear of contrast agent reactions. However, all subjects tolerated the injections well and had a quick recovery after sedation; therefore, intubation was not used for contrast-enhanced sonography in the recovery phase.…”