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Definity

CLINICAL PHARMACOLOGY

Mechanism of Action

Perflutren lipid microspheres exhibit lower acoustic impedance than blood and enhance the intrinsic backscatter of blood. These physical acoustic properties of activated DEFINITY® provide contrast enhancement of the left ventricular chamber and aid delineation of the left ventricular endocardial border during echocardiography.

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.

Pharmacokinetics

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

Distribution

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 mono-exponential fashion with a mean half-life of 1.3 minutes in healthy subjects.

Special Populations

The pharmacokinetics of octafluoropropane gas (OFP) was 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.

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

Clinical Studies

Echocardiography

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).

Activated DEFINITY® was evaluated in four controlled clinical trials: Two open-label baseline controlled, unpaired blinded image evaluation studies and two identical placebo-controlled, unpaired blinded image evaluation studies. Subjects were eligible for these studies if they had two or more (of six) non-evaluable segments in either the apical 2- or 4chamber view in non-contrast fundamental echocardiography.

In the baseline controlled studies, a total of 126 (67 in study A and 59 in study B) subjects received a bolus dose of 10 microL/kg activated DEFINITY®. The outcome measures in these studies included the blinded assessment of ejection fraction (EF), endocardial border length (EBL) obtained by direct measurement, and qualitative assessment of wall motion.

In the two placebo-controlled studies a total of 123 subjects were randomized in 1:2 ratio to receive two IV bolus doses of either saline (placebo) or activated DEFINITY® 10 microL/kg (17 placebo vs. 33 activated DEFINITY® patients and 24 placebo vs. 49 activated DEFINITY® patients, respectively). The outcome measure for assessing the effectiveness of activated DEFINITY® was the blinded assessment of improvement in ventricular chamber enhancement (measured by videodensitometry at end-diastole and end-systole).

Endocardial Border Length

As shown in Table 14.1, compared to baseline, a single bolus dose of 10 microL/kg of activated DEFINITY® increased the length of endocardial border that could be measured at both end-systole and end-diastole. The mean change in border length from baseline at end-diastole was statistically significant for all readers in the apical 4-chamber view and for 3 out of 4 readers for the apical 2-chamber view. The mean change in border length from baseline at end-systole was statistically significant for 3 out of 4 readers for the apical 4-chamber view and for 2 out 4 readers for the apical 2-chamber view.

Ventricular Chamber Enhancement

Left ventricular chamber enhancement after an activated DEFINITY® dose of 10 microL/kg was significantly increased from baseline compared to placebo in both views at the mid-ventricular and apical levels at end-diastole. Similar results were noted at end-systole, with the exception of the 4-chamber view.

Wall Motion

In a retrospective analysis, in a subset of subjects (n=12 to 47, depending on reader) having at least 2 adjacent segments non-evaluable on non-contrast imaging, activated DEFINITY® converted a baseline non-evaluable image to an evaluable image in 58 to 91% of the patients, depending on the reader. In the converted images, the accuracy of wall motion (i.e., normal versus abnormal) improved in 42 to 71% of the patients, depending on the reader, however, improvement in the specific diagnostic accuracy (e.g., hypokinetic, akinetic etc.) was not established. Also, in 13 to 37% of the patients, depending on the reader, activated DEFINITY® was found to obscure the wall motion rendering the image non-evaluable.

Ejection Fraction

In the 2 baseline controlled studies, ejection fraction results were evaluated in comparison to MRI. The results were evaluated by 3 blinded, independent radiologists. In these studies, although there was a statistically significant increase in ventricular chamber enhancement, activated DEFINITY® did not significantly improve the assessment of ejection fraction compared to the baseline images.

Table 14.1: MEAN (SD) ENDOCARDIAL BORDER LENGTH (CM) BY BOTH APICAL 2- AND 4-CHAMBER VIEWS AT END-SYSTOLE AND ENDDIASTOLE BY STUDY, EVALUABLE SUBJECTS

Study/View Endocardial Border Length –Blinded Read
Mean (SD) at End-Diastole Mean (SD) at End-Systole
Reader 1 Reader 2 Reader 1 Reader 2
Study A: (N = 67)
Apical 2-chamber
  Baseline 8.0 (3.4) 4.7 (2.8) 7.1 (3.3) 4.3 (2.6)
  Post-DEFINITY® 12.8 (5.2)* 5.8 (2.6)* 10.6 (5.0)* 4.4 (2.3)
Apical 4-chamber
  Baseline 8.1 (3.3) 4.5 (2.6) 7.6 (3.2) 4.5 (2.7)
  Post-DEFINITY® 13.5 (5.2)* 6.8 (3.3)* 11.5 (4.4)* 5.3 (3.1)
Study B: (N = 59)
Apical 2-chamber
  Baseline 4.3 (2.6) 7.8 (5.3) 4.1 (2.4) 6.5 (5.1)
  Post-DEFINITY® 5.7 (4.7)* 8.2 (6.5) 5.5 (4.4)* 6.9 (6.3)
Apical 4-chamber
  Baseline 4.0 (2.7) 9.2 (5.9) 3.8 (2.6) 7.3 (5.6)
  Post-DEFINITY® 7.1 (5.5)* 11.5 (7.5)* 5.9 (5.3)* 8.7 (6.3)*
Activated DEFINITY® Bolus Dose = 10 μL/kg
* Significant change from baseline (paired t-test, p < 0.05)

In an open administration, crossover trial, 64 patients were randomized to receive both bolus (10 microL/kg) and infusion (1.3 mL activated DEFINITY® in 50 mL saline at the rate of 4 mL/min) dosing of activated DEFINITY®. Outcome measures for this study included clinically useful ventricular cavity enhancement and endocardial border length. Similar results were seen as described above.

Optimal activated DEFINITY® doses and device settings for harmonic imaging have not been established.

Pulmonary Hemodynamic Effects

The impact of DEFINITY® on pulmonary hemodynamics was explored in a prospective, open-label study of patients with normal ( ≤ 35 mmHg, 16 patients) and elevated ( > 35 mmHg, < 75 mmHg, 16 patients) pulmonary artery systolic pressure undergoing right heart catheterization. Patients with pulmonary artery systolic pressure greater than 75 mmHg were excluded from this study. Systemic hemodynamic parameters and ECGs were also evaluated. No clinically important pulmonary hemodynamic, systemic hemodynamic, or ECG changes were observed. This study did not assess the effect of DEFINITY® on visualization of cardiac or pulmonary structures.

Last reviewed on RxList: 11/4/2011
This monograph has been modified to include the generic and brand name in many instances.

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