CLINICAL PHARMACOLOGY
General
Technetium Tc99m Sestamibi is a cationic Tc99m complex which has been found to accumulate in viable myocardial tissue in a manner analogous to that of thallous chloride Tl-201. Scintigraphic images obtained in humans after the intravenous administration of the drug have been comparable to those obtained with thallous chloride Tl-201 in normal and abnormal myocardial tissue.
Animal studies have shown that myocardial uptake is not blocked when the sodium pump mechanism is inhibited. Although studies of sub cellular fractionation and electron micrographic analysis of heart cell aggregates suggest that Tc99m Sestamibi cellular retention occurs specifically within the mitochondria as a result of electrostatic interactions, the clinical relevance of these findings has not been determined.
The mechanism of Tc99m Sestamibi localization in various types of breast tissue (e.g., benign, inflammatory, malignant, fibrous) has not been established.
Pharmacokinetics
Pulmonary activity is negligible even immediately after injection. Blood clearance
studies indicate that the fast clearing component clears with a t1/2
of 4.3 minutes at rest, and clears with a t1/2 of 1.6 minutes under
exercise conditions. At five minutes post injection about 8% of the injected
dose remains in circulation. There is less than 1% protein binding of Technetium
Tc99m Sestamibi in plasma. The myocardial biological half-life is approximately
six hours after a rest or exercise injection. The biological half-life for the
liver is approximately 30 minutes after a rest or exercise injection. The effective
half-life of clearance (which includes both the biological half-life and radio nuclide
decay) for the heart is approximately 3 hours, and for the liver is approximately
30 minutes, after a rest or exercise injection. The ideal imaging time reflects
the best compromise between heart count rate and surrounding organ uptake.
Myocardial uptake which is coronary flow dependent is 1.2% of the injected dose at rest and 1.5% of the injected dose at exercise. Table 7.0 illustrates the biological clearance as well as effective clearance (which includes biological clearance and radio nuclide decay) of Tc99m Sestamibi from the heart and liver.
[Organ concentrations expressed as percentage of injected dose; data based on an average of 5 subjects at rest and 5 subjects during exercise].
Table 7.0
|
REST |
STRESS |
|
Heart |
Liver |
Heart |
Liver |
Time |
Biological |
Effective |
Biological |
Effective |
Biological |
Effective |
Biological |
Effective |
5 min. |
1.2 |
1.2 |
19.6 |
19.4 |
1.5 |
1.5 |
5.9 |
5.8 |
30min. |
1.1 |
1.0 |
12.2 |
11.5 |
1.4 |
1.3 |
4.5 |
4.2 |
1 hour |
1.0 |
0.9 |
5.6 |
5.0 |
1.4 |
1.2 |
2.4 |
2.1 |
2 hours |
1.0 |
0.8 |
2.2 |
1.7 |
1.2 |
1.0 |
0.9 |
0.7 |
4 hours |
0.8 |
0.5 |
0.7 |
0.4 |
1.0 |
0.6 |
0.3 |
0.2 |
A study in a dog myocardial ischemia model reported that Technetium Tc99m Sestamibi undergoes myocardial distribution (redistribution), although more slowly and less completely than thallous chloride Tl-201. A study in a dog myocardial infarction model reported that the drug showed no redistribution of any consequence. Definitive human studies to demonstrate possible redistribution have not been reported. In patients with documented myocardial infarction, imaging revealed the infarct up to four hours post dose.
Metabolism
The agent is excreted without any evidence of metabolism.
Elimination
The major pathway for clearance of Tc99m Sestamibi is the hepatobiliary system. Activity from the gall bladder appears in the intestines within one hour of injection. Twenty-seven percent of the injected dose is excreted in the urine, and approximately thirty-three percent of the injected dose is cleared through the feces in 48 hours.
Clinical Studies
Clinical Trials: MYOCARDIAL IMAGING: In a trial of rest and stress CARDIOLITE®
imaging, the relationship of normal or abnormal perfusion scans and long term
cardiac events was evaluated in 521 patients (511 men, 10 women) with stable
chest pain. There were 73.9% Caucasians, 25.9% Blacks and 0.2% Asians. The mean
age was 59.6 years (range: 29 to 84 years). All patients had a baseline rest
and exercise CARDIOLITE® scan and were followed for 13.2 ± 4.9 months (range:
1 to 24 months). Images were correlated with the occurrence of a cardiac event
(cardiac death or non-fatal myocardial infarction). In this trial as summarized
in Table 8.0, 24/521 (4.6%) had a cardiac event.
Table 8.0 - Cardiac Events
Baseline Scan (a) |
Proportion of patients with events by scan
results (a) |
Proportion of scan result in patients with
events; N=24 (a) |
Proportion of event-free patients by scan
result (a) |
Normal |
1/206 (0.5%) |
1/24 (4.2%) |
205/206 (99.5%) |
Abnormal |
23/315 (7.3%) (b) |
23/24 (95.8%) (b) |
292/315 (92.7%) (b) |
(a) Note: Similar findings were found in two
studies with patients who had pharmacologic stress CARDIOLITE® imaging.
(b) p < 0.0l |
Although patients with normal images had a lower cardiac event rate than those with abnormal images, in all patients with abnormal images it was not possible to predict which patient would be likely to have further cardiac events; i.e., such individuals were not distinguishable from other patients with abnormal images.
The findings were not evaluated for defect location, disease duration, specific vessel involvement or intervening management.
In earlier trials, using a template consisting of the anterior wall, inferior-posterior wall and isolated apex, localization in the anterior or inferior-posterior wall in patients with suspected angina or coronary artery disease was shown. Disease localization isolated to the apex has not been established. In adults, Tc99m Sestamibi has not been studied or evaluated in cardiac disorders other than coronary artery disease.
Breast Imaging: MIRALUMA® (technetium tc99m sestamibi) was evaluated in two multicenter, clinical
trials of a total of 673 woman patients. Overall the mean age was 52 (range
23 to 87 years). The racial and ethnic representation was 70% Caucasian, 15%
African-American, 14% Hispanic and 1% Asian.
Both clinical studies evaluated women who were referred for further evaluation for either: 1) a mammographically detected (with varying degrees of malignant likelihood) but not palpable breast lesion (study A, n=387, mean age = 54 years), or 2) a palpable breast lesion (study B, n=286, mean age = 50 years). In both studies all patients were scheduled for biopsy.
MIRALUMA® (technetium tc99m sestamibi) (20-30 mCi) was injected intravenously in a vein that was contralateral
to the breast lesion in question. Planar imaging was completed with a high resolution
collimator with a 10% window centered at 140 KeV, and 128 x 128 matrix. An initial
marker image, that was not used in the data analysis, was obtained using a cobalt
Co57 point source as a marker of a palpable mass. Images were obtained 5 minutes
after injection as follows: lateral image of the affected breast for 10 minutes,
lateral image of the contralateral breast for 10 minutes, and an anterior image
of both breasts for 10 minutes. For the lateral image the patients were positioned
in a prone position. For the anterior image, the patients were supine. The MIRALUMA® (technetium tc99m sestamibi)
scintigraphic images were read in a randomized method by two groups of three
blinded readers. MIRALUMA® (technetium tc99m sestamibi) uptake was scored as: normal (no uptake), equivocal,
low, moderate, or high uptake. The results of MIRALUMA® (technetium tc99m sestamibi) images and mammography
were analyzed in comparison to histopathologic findings of malignant or non-malignant
disease.
As shown in Table 9.0 for the 483 evaluable patients, the sensitivity and specificity of any degree of MIRALUMA® (technetium tc99m sestamibi) uptake appear to vary with the presence or absence of palpable mass.
TABLE 9.0 - Overall MIRALUMA® (technetium tc99m sestamibi) Blinded Results of Target
Lesions (a) Identified at Study Entry (b)
STATISTIC |
Study A
Non-Palpable Mass and an Abnormal Mammogram |
Study B
Palpable Mass |
Number of Patients and Lesions |
N=277
Patients with 300 Lesions |
N-206
Patients with 240 Lesions |
Sensitivity |
52 (42,62) (c) |
76 (67,83) |
Specificity |
94 (89,96) |
85 (77,91) |
PPV (d) |
79 (67,88) |
83 (74,89) |
NPV (d) |
80 (74,85) |
78 (69,84) |
Agreement |
80 (75,85) |
80 (75,85) |
Prevalence |
32 (27,37) |
49 (43,56) |
(a) Excludes all discordant lesions not identified at entry
and excludes 25 equivocal interpretations from Study A and 32 equivocal
interpretations from Study B (see Tables 10.0 and 11.0)
(b) some patients had more than one target lesion
(c) Median and approximated 95% Confidence Interval
(d) PPV= Positive Predict Value; NPV= Negative Predict Value |
In a separate retrospective subset analyses of 259 patients with dense (heterogeneously/extremely dense) and 275 patients with fatty (almost entirely fat/numerous vague densities) breast tissue, the MIRALUMA® (technetium tc99m sestamibi) results were similar. Overall, the studies were not designed to compare the performance of MIRALUMA® (technetium tc99m sestamibi) with the performance of mammography in patients with breast densities or other coexistent breast tissue disorders.
In general the histology seems to correlate with the degree of MIRALUMA® (technetium tc99m sestamibi)
uptake. As shown in Tables 10.0 and 11.0, the majority of the normal MIRALUMA® (technetium tc99m sestamibi)
images are associated with non-malignant tissue (78-81%) and the majority of
low, moderate or high uptake MIRALUMA® (technetium tc99m sestamibi) images are associated with malignant
disease (79-83%). In an individual patient, however, the intensity of MIRALUMA® (technetium tc99m sestamibi)
uptake can not be used to confirm the presence or absence of malignancy. Equivocal
results do not have a correlation with histology.
TABLE 10.0 - Degree of MIRALUMA® (technetium tc99m sestamibi) Breast Imaging Uptake
in Comparison to Histopathology Results in Patients with Mammographically Detected
Non-Palpable Lesions* (Study A)
|
Normal Uptake
N = 249 lesions |
Equivocal Uptake
N = 25 lesions |
Low, Moderate or High Uptake
N = 66 lesions |
Non-malignant** |
201 (81%) |
14 (56%) |
14 (21%) |
Malignant |
48 (19%) |
11 (44%) |
52 (79%) |
* Median finding for 3 blinded readers
** Includes benign tissue, fibroadenoma, benign intra mammary nodes, radial
scar. |
TABLE 11.0 - Degree of MIRALUMA® (technetium tc99m sestamibi) Breast Imaging Uptake
in Comparison to Histopathology Results in Patients with Palpable Lesions* (Study
B)
|
Normal Uptake
N = 129 lesions |
Equivocal Uptake
N = 32 lesions |
Low, Moderate or HighUptake
N = 115 lesions |
Non-malignant** |
100 (78%) |
19 (59%) |
20 (17%) |
Malignant |
29 (22%) |
13 (41%) |
95 (83%) |
* Median finding for 3 blinded readers
** Includes benign tissue, fibroadenoma, benign intra mammary nodes, radial
scar. |
An estimate of the likelihood of malignancy based on the MIRALUMA® (technetium tc99m sestamibi) uptake
score in combination with the mammographic score has not been studied.
In these two studies approximately 150 additional, non-biopsied lesions were
found to be positive after MIRALUMA® (technetium tc99m sestamibi) imaging. These lesions were identified
in sites that did not physically correlate with identified entry criteria mammographic
lesions and these lesions were not palpable. These lesions were not biopsied.
Whether these lesions were benign or malignant is not known. MIRALUMA® (technetium tc99m sestamibi) uptake
can occur in both benign and malignant disease. THE CLINICAL USEFULNESS OF
A POSITIVE MIRALUMA® (technetium tc99m sestamibi) IMAGE IN THE ABSENCE OF AN ABNORMAL MAMMOGRAM OR A
PALPABLE LESION IS NOT KNOWN.