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Optison

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Optison

CLINICAL PHARMACOLOGY

General

The OPTISON microspheres create an echogenic contrast effect in the blood.

Pharmacokinetics

Studies in humans have evaluated the pharmacokinetics of the perflutren component of the OPTISON microspheres. After injection of OPTISON, diffusion of the perflutren gas out of the microspheres is limited by the low partition coefficient of the gas in blood that contributes to the persistence of the microspheres. The diffusion rate has not been studied.

In an anesthetized dog model, the acoustic properties of OPTISON were established at 0.6 mechanical index and 2.5 MHz frequency.

Neither the pharmacokinetics of the intact microspheres or of the human albumin component have been evaluated in humans.

Metabolism

Perflutren is a stable gas that is not metabolized. The human albumin component of the microsphere is expected to be handled by the normal metabolic routes for human albumin.

Perflutren Elimination

Following a single intravenous dose of 20 mL OPTISON to 10 healthy volunteers (5 men and 5 women), most of the perflutren was eliminated through the lungs within 10 minutes. The recovery was 96% ± 23% (mean ± SD), and the pulmonary elimination half-life was 1.3 ± 0.69 minutes (mean ± SD). The perflutren concentration in expired air peaked approximately 30-40 seconds after administration.

Perflutren Protein Binding

The binding of perflutren to plasma proteins or its partitioning into blood cells have not been studied. However, perflutren protein binding is expected to be minimal due to the low partition coefficient of the gas in blood.

Special Populations

The pharmacokinetics of OPTISON have not been studied in patients with hepatic or respiratory diseases.

Gender, Age, Race

The effects of gender, age, or race on the pharmacokinetics of OPTISON have not been studied.

Drug-Drug Interactions

Drug-drug interactions for OPTISON have not been studied.

Pediatrics

The pharmacokinetics of OPTISON in pediatric patients have not been studied.

Pharmocodynamics

The general acoustic properties of OPTISON are similar to those of ALBUNEX®. The acoustic impedance of the OPTISON microspheres is much lower than that of the blood. Therefore, impinging ultrasound waves are scattered and reflected at the microsphere-blood interface and ultimately may be visualized in the ultrasound image. At the frequencies used in adult echocardiography (2-5 MHz), the microspheres resonate which further increases the extent of ultrasound scattering and reflection.

As assessed by the unblinded investigators in clinical studies, the median duration of OPTISON contrast enhancement for each of the four doses of OPTISON (0.2, 0.5, 3.0, and 5.0 mL) were approximately one, two, four, and five minutes, respectively (see Clinical Trials section).

Clinical Trials

Echocardiography

The efficacy of OPTISON was evaluated in two identical multicenter, dose escalation, randomized, cross-over studies of OPTISON and ALBUNEX®. The test drugs were administered single blind and the image analysis was double blind. Eligible patients were undergoing routine echocardiography and all patients were required to have at least two of six segments of the left ventricular endocardial border that were not well delineated in the apical 4-chamber view. In these studies, the 203 patients (Study A: n=101, Study B: n=102) received at least one dose of study drug had the following characteristics: 79% men, 21% women, 64% White, 25% Black, 10% Hispanic, and 1% other race or ethnic group. The patients had a mean age of 61 years (range: 21 to 83 years), a mean weight of 196 Ibs (range: 117 to 342 Ibs), a mean height of 68 inches (range: 47 to 78 inches), and a mean body surface area of 2.0m2 (range: 1.4 to 2.6m2). Approximately 23% of the patients had chronic pulmonary disease, and 17% had congestive and dilated cardiomyopathy with left ventricular ejection fractions (LVEFs) of between 20% and 40% (by previous echocardiography). Patients with a LVEF of less than 20% or with New York Heart Association Class IV heart failure were not included in the studies.

The study test drugs were four doses of OPTISON (0.2, 0.5, 3.0 and 5.0 mL) and two doses of ALBUNEX® (0.08 and 0.22 mL/kg). The two test drugs were administered to the patients in a random sequence, with two to ten days between each drug. After non-contrast imaging, the test doses were administered in ascending order with at least ten minutes between each dose. Ultrasound settings were optimized for the baseline (non-contrast) apical four-chamber view and remained unchanged for the contrast imaging. Static echocardiographic images and video-tape segments were interpreted by a reader who was blinded to the patient's clinical history and to the identity and dose of the test drug. The primary efficacy endpoint was left ventricular endocardial border delineation, assessed before and after OPTISON administration, by the measurement of visualized endocardial border length. The six segments of the left ventricular endocardial border were also assessed qualitatively (i.e., not well delineated, average delineation, good delineation, excellent delineation) before and after OPTISON administration.

In comparison to non-contrast ultrasound, OPTISON significantly increased the length of endocardial border that could be visualized both at end-systole and end-diastole (see Table 2). In these patients there was a trend towards less visualization in women. Similarly, in comparison to non-contrast ultrasound, OPTISON significantly improved the qualitative ability to delineate each of the left ventricular segments, though the effect was less for the septal segments. As assessed by videodensitometry, OPTISON increased left ventricular opacification (peak intensity) in the mid-chamber and apical views (see Table 3). In subset analysis, OPTISON tended to enhance the quality of the spectral Doppler signal of the pulmonary veins. The imaging effects of OPTISON on endocardial border delineation and left ventricular opacification tended to be qualitatively similar in patients with and without pulmonary disease or dilated cardiomyopathy.

In these studies, quantitative measures of left ventricular function (e.g., ejection fraction), quantitative measurements of anatomical structures (e.g., wall thickness), or the evaluation of myocardial perfusion were not performed.

Table 2: Left Ventricular Endocardial Border Length Before and After OPTISONa,b

  Length at End- Systole (cm) Length at End-Diastole (cm)
OPTISON dose n mean ± S.D. n mean
Study A (n=101)        
0 mL (baseline) 87 7.7 ±3.0 86 9.3 ±3.4
0.2 mL 85 11.7 ±4.3 85 15.7 ±3. 8
0.5 mL 86 12.0 ±4.9 91 15.8±5.1
3.0 mL 87 12.3 ±4.4 88 16.7 ±4.0
5.0 mL 89 12.7 ±4.9 90 16.6 ±4.3
Study B (n=102)        
0 mL (baseline) 89 8.1 ±3.4 89 9.6 ±3.7
0.2 mL 90 11.3 ±4.5 95 15.0 ±5.3
0.5 mL 95 12.4 ±4.9 97 16.4 ±4.6
3.0 mL 94 12.6 ±4.8 99 16.5 ±4.7
5.0 mL 92 13.0 ±4.5 95 16.2 ±5.1
a The differences in the number of enrolled patients and evaluated patients at each dose reflects exclusions based on withdrawal from the trial, or those with technically inadequate or missing images.
b An intent-to-treat analysis, with non-favorable values imputed for missing patients, provided qualitatively similar results.

Table 3: Intensity of Left Ventricular Gratificationa Before and After OPTISON™ b,c

  Mid-Chamber Apex
  Intensity at End-Diastole Intensity at End- Systole Intensity at End-Diastole Intensity at End-Systole
OPTISON dose n mean ± S.D. n mean ± S.D. n mean ± S.D. n mean ± S.D.
Study A (n= 101)
0 mL (baseline) 91 39.5 ± 16.9 91 40.0 ± 18.1 91 46.7 ± 19.7 91 46.9 ± 20.1
0.2 mL 91 56.7 ± 26.2 91 55.4 ± 26.6 91 63.2 ± 28.9 91 61.1 ± 28.5
0.5 mL 91 57.3 ± 26.8 90 57.4 ± 26.7 91 67.0 ± 30.1 90 64.1 ± 30.2
3.0 mL 90 53.9 ± 22.5 90 55.8 ± 24.3 90 66.1 ± 28.2 90 61.8 ± 26.8
5.0 mL 89 54.7 ± 24.0 89 57.9 ± 28.3 89 69.1 ± 30.4 89 63.7 ± 28.9
Study B (n= 102)
0 mL (baseline) 95 40.4 ± 17.4 95 40.9 ± 17.5 95 43.7 ± 19.9 95 45.0 ± 19.6
0.2 mL 97 52.5 ± 21.0 97 5 1.5 ± 20.6 97 58.4 ± 22.2 97 56.0 ± 22.2
0.5 mL 97 53.3 ± 20.7 96 53.6 ± 21.0 97 64.4 ± 25.3 96 6 1.6 ± 26.7
3.0 mL 99 5 1.2 ± 23.6 99 55.6 ± 24.5 99 65.4 ± 26.3 99 62.7 ± 25.7
5.0 mL 95 51.8 ± 23.8 95 55.6 ± 24.8 95 65.2 ± 28.1 95 62.8 ± 28.1
a Intensity measured by videodensitometry in arbitrary gray scale units (0-255).
b The differences in the number of enrolled patients and evaluated patients at each dose reflects exclusions based on withdrawal from the trial, or those with technically inadequate or missing images.
c An intent-to-treat analysis, with non-favorable values imputed for missing patients, provided qualitatively similar results.

Pulmonary Hemodynamic Effects

The effect of OPTISON on pulmonary hemodynamics was studied in a prospective, open-label study of 30 patients scheduled for pulmonary artery catheterization, including 19 with an elevated baseline pulmonary arterial systolic pressure (PASP) ( > 35 mmHg) and 11 with a normal PASP ( ≤ 35 mmHg). 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 OPTISON on visualization of cardiac or pulmonary structures.

Last reviewed on RxList: 9/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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