Pharmacodynamics

After activation of DEFINITY® and intravenous injection, the physical acoustic properties of activated DEFINITY® (see DESCRIPTION) provide contrast enhancement of the endocardial borders during echocardiography. The perflutren lipid microspheres exhibit lower acoustic impedance than blood and enhance the intrinsic backscatter of blood.

In animal models the acoustic properties of activated DEFINITY® were established at or below a mechanical index of 0.7 (1.8 MHz frequency). In clinical trials, the majority of the patients were imaged at or below a mechanical index of 0.8.

In a crossover trial of 64 patients randomized to both bolus and infusion, the duration of clinically useful contrast enhancement for fundamental imaging was approximately 3.4 minutes after a 10 ìL/kg bolus and was approximately 7.1 minutes during the continuous infusion of 1.3 mL activated DEFINITY® in 50 mL saline at a rate of 4 mL/min.

Pharmacokinetics

Human pharmacokinetics information is not available for the intact or degassed lipid microspheres. The pharmacokinetics of octafluoropropane gas (OFP) were evaluated in healthy subjects (n=8) after the IV administration of activated DEFINITY® at a 50 ìL/kg dose.

Octafluoropropane (OFP) Protein Binding OFP gas binding to plasma proteins or partitioning into blood cells has not been studied. However, OFP protein binding is expected to be minimal due to its low partition coefficient into whole blood.

Metabolism

OFP is a stable gas that is not metabolized. The phospholipid components of the microspheres are thought to be metabolized to free fatty acids.

Elimination

OFP was not detectable after 10 minutes in most subjects either in the blood or in expired air. OFP concentrations in blood were shown to decline in a monoexponential fashion with a mean half-life of 1.3 minutes in healthy subjects.

Special Populations

The pharmacokinetics of octafluoropropane gas (OFP) were evaluated in subjects (n=11) with chronic obstructive pulmonary disease (COPD). The mean half-life of OFP in blood was 1.9 minutes. The total lung clearance of OFP was similar to that in healthy subjects.

Microspheres may obstruct the vasculature of some patients. See WARNINGS for use in subjects with cardiac shunts and pulmonary hypertension.

The pharmacokinetics of activated DEFINITY® has not been studied in subjects with hepatic diseases or congestive heart failure.

Gender

The effects of activated DEFINITY® appeared to be similar in men and women.

Age/Race

The effects of age and race on the pharmacokinetics of activated DEFINITY® have not been studied.

Pediatrics

The pharmacokinetics of activated DEFINITY® in pediatric subjects has not been studied. The safety of injecting activated DEFINITY® in neonates and infants with immature pulmonary vasculature has not been studied (see WARNINGS).

Elderly

The pharmacokinetics of activated DEFINITY® in the elderly has not been studied.

Drug -Drug Interactions

Drug-drug interactions for activated DEFINITY® have not been studied.

Clinical Trials

A total of 249 subjects were evaluated in clinical trials (208 received activated DEFINITY® and 41 placebo). In this group, 154 (61.8%) were male and 95 (38.2%) were female; 183 (73.5%) were White, 38 (15.3%) were Black, 21 (8.4%) were Hispanic, and 7 (2.8%) were classified as other racial or ethnic groups. The mean age was 53.9 years (range 18 to 87).

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