Quadramet (Page 2 of 5)

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 t 1/2 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 pharmacokinetics, the cumulative % of radioactivity excreted in urine, or the % radioactivity retained in the skeleton when the number of metastatic lesions is taken into account.

Specific 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 Impairment

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 Impairment

Patients with renal impairment have not been studied. Because approximately one third of Samarium Sm-153 EDTMP is excreted in the urine, clearance may be reduced in patients with renal impairment; it is not known if dose adjustment is needed.

Drug/Drug Interaction

Drug-drug interaction studies have not been studied.

Pharmacodynamics

The beta particle of 153 Sm-EDTMP travels a maximum distance of 3.0 mm in soft tissue and 1.7 mm in bone. In clinical trials of 78 patients with metastatic bone lesions who had 13 specific bone scan sites evaluated, the presence or absence of 153 Sm-EDTMP uptake is similar to the presence or absence of 99m Tc diphosphonate uptake (range 67 to 96% agreement depending upon the blinded reader and the site of the body). Whether the amount of 153 Sm-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 radionuclide 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 analogue 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 WEEKLY PAIN SCORES * AFTER QUADRAMET® 1.0mCi/kg or PLACEBO IV [Intent to Treat]
STUDY A (n = 73) STUDY B (n = 150)
WEEK PlaceboN=36 1.0 mCi/kgN=37 PlaceboN=50 1.0 mCi/kgN=100
*
Area Under the Pain Curve (SD).
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.
Excludes 2 patients with missing baseline values.
§
Statistically significant difference in change from baseline in comparison to placebo.
Baseline 26.5 (11.8) 28.7 (12.3) 28.5 (14.1) 28.1 (12.9)
1 26.1 (10.3) 27.6 (14.1) 27.9 (14.6) 25.8 (13.1)
2 24.4 (10.4) 23.8 (13.7) 28.1 (15.4) 20.6 (13.9)§
3 24.3 (11.0) 20.5 (11.5)§ 25.8 (16.1) 20.1 (13.3)§
4 24.7 (12.1) 18.8 (10.8)§ 24.7 (15.3) 19.9 (13.7)§

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: COMPARISON OF WEEKLY MEAN ANALGESIC USE * BETWEEN QUADRAMET® 1.0 mCi/kg AND PLACEBO GROUPS [Intent to Treat]
STUDY A (n = 73) STUDY B (n = 150)
WEEK PlaceboN=36 1.0 mCi/kgN=37 PlaceboN=50 1.0 mCi/kgN=100
*
Mean Analgesic Use (SD) is in morphine equivalent units; 0 = none.
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.
Excludes 2 patients with missing baseline values.
§
Statistically significant difference in change from baseline in comparison to placebo.
Baseline 93.5 (154.0) * 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)§

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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