A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Quadramet Pharmacology, Pharmacokinetics, Studies, Metabolism - Samarium SM 153 Lexidronam
Quadramet Pharmacology, Pharmacokinetics, Studies, Metabolism - Samarium SM 153 Lexidronam
CLINICAL PHARMACOLOGY
Quadramet (samarium Sm-153 EDTMP) has an affinity for bone
and concentrates in areas of bone turnover in association with hydroxya-patite.
In clinical studies employing planar imaging techniques, more Quadramet accumulates
in osteoblastic lesions than in normal bone with a lesion-to-normal bone ratio
of approximately 5. The mechanism of action of Quadramet in relieving the pain
of bone me-tastases is not known.
Distribution: Human protein binding has not been studied;
however, in dog, rat and bovine studies, less than 0.5% of samarium-153 EDTMP
is bound to protein. At physiologic pH, >90% of the complex is present as
153Sm[EDTMP]-5, and <10% as 153SmH[EDTMP]-4.
The octanol/ water partition coefficient is <10-5.
Skeletal Uptake: The greater the number of metastatic
lesions, the more skeletal uptake of Sm-153 radioactivity. The relationship
between skeletal uptake and the size of the metastatic lesions has not been
studied. The total skeletal uptake of radioactivity was 65.5% ± 15.5% of the
injected dose in 453 patients with meta-static lesions from a variety of primary
malignancies. In a study of 22 patients with a wide range in the number of metastatic
sites, the % of the injected dose (% ID) taken up by bone ranged from 56.3%
in a patient with 5 meta-static lesions to 76.7% in a patient with 52 metastatic
lesions. If the number of metastatic lesions is fixed, over the range 0.1 to
3.0 mCi/ kg, the % ID taken up by bone is the same regardless of the dose.
Metabolism: The complex formed by samarium and EDTMP
is excreted as an intact, single species that consists of one atom of the Sm-153
and one molecule of the EDTMP, as shown by an analysis of urine samples from
patients (n=5) administered samarium Sm-153 EDTMP. Metabolic products of samarium
Sm-153 EDTMP were not detected in humans.
Elimination: For Quadramet, calculations of the % ID
detected in the whole body, urine and blood were corrected for radionuclide
decay. The clearance of activity through the urine is expressed as the cumulated
activity excreted. The whole body retention is the simple reciprocal of the
cumulated urine activity. (See Skeletal Uptake Section).
Blood: Clearance of radioactivity from the blood demonstrated
biexponential kinetics after intravenous injection in 19 patients (10 men, 9
women) with a variety of primary cancers that were metastatic to bone. Over
the first 30 minutes, the radioactivity (mean ± SD) in the blood decreased to
15% (±8%) of the injected dose with a t1/2 of 5.5 min (±1.1 min).
After 30 minutes, the radioactivity cleared from the blood more slowly with
a t1/2 of 65.4 min (± 9.6 min). Less than 1% of the dose injected
remained in the blood 5 hr after injection.
Urine: Samarium Sm-153 EDTMP radioactivity was excreted in
the urine after intravenous injection. During the first 6 hours, 34.5% (±15.5%)
was excreted. Overall, the greater the number of metastatic lesions, the less
radioactivity was excreted.
Gender Differences: Gender did not affect the samarium
Sm-153 EDTMP blood pharmacoki-netics, the cumulative % of radioactivity excreted
in urine, or the % radioactivity retained in the skeleton when the number of
metastatic lesions is taken into account.
Special Populations
Elderly: The pharmacokinetics of samarium Sm-153 EDTMP did
not change with age as seen from comparison of values from people in the age
range of 22 to 64 compared to the range 65 to 86 years.
Hepatic Insufficiency: Samarium Sm-153 EDTMP scintiscans in
5 patients with metastatic bone disease did not reveal accumulation of activity
in the liver or the intestine; this suggests that hepatobiliary excretion did
not occur.
Renal Insufficiency: Patients with renal insufficiency have
not been studied.
Drug/Drug Interaction
Drug-drug interaction studies have not been studied.
Pharmacodynamics
The beta particle of 153Sm-EDTMP travels an average
of 3.1 mm in soft tissue and 1.7 mm in bone. In clinical trials of 78 patients
with meta-static bone lesions who had 13 specific bone scan sites evaluated,
the presence or absence of 153Sm-EDTMP uptake is similar to the presence
or absence of 99mTc diphosphonate uptake (range 67 to 96% agreement
depending upon the blinded reader and the site of the body). Whether the amount
of 153Sm-EDTMP uptake varies with the size of the lesion or to the
presence of osteolytic components has not been studied. The clinical benefit
of Sm-153-EDTMP in patients with osteolytic lesions is not known. The relationship
of different tumor cell types to clinical response has not been studied.
CLINICAL TRIALS
Overall Quadramet was evaluated in 580 patients (see Adverse
Events Section for demographic description). Of these patients, 270 (244 men,
26 women) were studied in two randomized, blinded, placebo controlled clinical
trials. These patients had a mean age of 67, and a range 22 to 87 years. Eligible
patients had painful metastatic bone lesions that had failed other treatments,
had at least a 6 month expected survival and had a positive radionu-clide bone
scan. Routine x-rays to evaluate the metastatic lesions were not part of the
protocol.
In study A, 118 patients were randomized to receive 0.5 mCi/kg
Quadramet, 1.0 mCi/kg Quadramet, or a placebo intravenous injection. In study
B, 152 patients were randomized to receive either 1.0 mCi/kg Quadramet or a
placebo intravenous injection. Both studies were double blind over a 4 week
period. Patients scored their daily pain intensity on a visual ana-logue scale
rated from 0 (no or low pain) to 10 (excruciating pain). The area under the
pain curve (AUPC) was obtained by integrating the daily pain scores by week.
Opioid analgesic use was recorded daily and averaged over each week and expressed
in oral morphine milligram equivalents.
Of the 270 patients studied, 232 (86%) had prostate cancer
and 38 (14%) had other primary cancers. In study A, 80 (68%) of the patients
had prostate cancer and 38 (32%) had a variety of other primary tumors. In study
B, all (100%) patients had prostate cancer.
The results of the patients’ AUPC scores are shown in Table
3. In both trials for each of the 4 weeks of study, the mean AUPC scores decreased
in patients who received Quadramet (1.0 mCi/kg). In study A, pain (the AUPC)
decrease from baseline was significantly different in Quadramet 1.0 mCi/kg and
placebo groups at weeks 3 and 4. In study B, pain (the AUPC) decrease from baseline
was significantly different in Quadramet 1.0 mCi/kg and placebo groups at weeks
2, 3 and 4.
|
TABLE 3: COMPARISON OF WEEK LY PAIN SCORES (a) AFTER
QUADRAMET 1.0 mCi/kg or PLACE BO IV [Intent to Treat]
|
| |
STUDY A (n = 73) (b)
|
STUDY B (n = 150) (c)
|
|
WEEK
|
Placebo N=36
|
1.0 mCi/kg N=37
|
Placebo N=50
|
1.0 mCi/kg N=100
|
|
Baseline
|
2 6.5 (11.8)
|
2 8.7 (12.3)
|
2 8.5 (14.1)
|
28.1 (12.9)
|
|
1
|
2 6.1 (10.3)
|
2 7.6 (14.1)
|
2 7.9 (14.6)
|
25.8 (13.1)
|
|
2
|
2 4.4 (10.4)
|
2 3.8 (13.7)
|
2 8.1 (15.4)
|
20.6 (13.9)*
|
|
3
|
2 4.3 (11.0)
|
2 0.5 (11.5)*
|
2 5.8 (16.1)
|
20.1 (13.3)*
|
|
4
|
2 4.7 (12.1)
|
1 8.8 (10.8)*
|
2 4.7 (15.3)
|
19.9 (13.7)*
|
(a) Area Under the Pain Curve (SD).
(b) Excludes 5 patients with missing baseline or extreme values;
and all 40 patients who received 0.5 mCi Quadramet. Quadramet 0.5 mCi/kg can
not be distinguished from placebo.
(c) Excludes 2 patients with missing baseline values.
(*) Statistically significant difference in change from baseline
in comparison to placebo.
In the two clinical trials, the patient use of analgesics differed.
In Study A, the patients did not receive specific instructions on analgesic
reduction. In Study B, patients were encouraged to adjust their pain medication
as needed. As shown in Table 4, the morphine equivalent analgesic use in study
A generally increased from baseline in both the Quadramet and placebo treatment
groups; however, the difference between the Quadramet and placebo group change
from baseline is not statistically significant. In study B, the placebo treated
patients increased their use of opioid analgesics, while the Quadramet treated
patients decreased their use of opioid analgesics.
|
TABLE 4: COMP ARISON OF WEEKL Y MEAN ANALG ESIC USE (a)
BET WEEN QUA DRAMET 1.0mCi/kg A ND PLACEBO GROUPS [Intent to Treat]
|
| |
STUDY A (n = 73) (b)
|
STUDY B (n = 150) (c)
|
|
WEEK
|
Placebo N=36
|
1.0 mCi/kg N=37
|
Placebo N=50
|
1.0 mCi/kg N=100
|
|
Baseline
|
93.5 (154.0)(a)
|
127.1 (189.9)
|
78.4 (83.1)
|
96.5 (166.6)
|
|
1
|
106.8 (173.8)
|
125.7 (192.6)
|
84.5 (91.1)
|
93.5 (165.5)
|
|
2
|
127.1 (238.4)
|
144.8 (276.7)
|
85.6 (90.9)
|
82.9 (122.9)
|
|
3
|
133.9 (254.0)
|
146.6 (278.2)
|
100.1 (119.4)
|
79.6 (131.2)*
|
|
4
|
135.6 (222.0)
|
135.1 (274.0)
|
106.3 (161.0)
|
76.8 (132.3)*
|
(a) Mean Analgesic Use (SD) is in morphine equivalent units;
0 = none.
(b) Excludes 5 patients with missing baseline or with extreme
values; and all 40 patients who received 0.5 mCi Quadramet. Quadramet 0.5 mCi/kg
can not be distinguished from placebo.
(c) Excludes 2 patients with missing baseline values.
(*) Statistically significant difference in change from baseline
in comparison to placebo.
In both studies, the numbers of patients who experienced any
decrease in AUPC score without any increase in analgesic use at weeks 3 and
4 were also evaluated. In study A, this occurred in 20/37 (54%) of the patients
who received Quadramet 1.0 mCi/kg and 9/36 (25%) of the placebo treated patients.
In study B, this occurred in 48/100 (48%) of the Quadramet treated patients
and 11/51 (22%) of the placebo treated patients.
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