Prescription Drug Information: Radiogardase (Page 2 of 3)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Prussian blue insoluble, ferric hexacyanoferrate(II), acts by ion-exchange, adsorption, and mechanical trapping within the crystal structure, and has a high affinity for radioactive and non-radioactive cesium and thallium.

Prussian blue insoluble binds cesium and thallium isotopes in the gastrointestinal tract after these isotopes are ingested or excreted in the bile by the liver, thereby reducing gastrointestinal reabsorption (enterohepatic circulation). The rate of cesium and thallium elimination is proportional to the duration and dose of prussian blue insoluble.

12.2 Pharmacodynamics

Cesium-137 ( 137 Cs)
137 Cs has a physical half-life of 30 years, with a beta energy peak at 174.0 keV. Following entry into the blood, it is distributed uniformly through all body tissues. Approximately 10% of 137 Cs is eliminated rapidly with a biological half-life of 2 days; 90% is eliminated more slowly, with a biological half-life of 110 days; and less than 1% of the 137 Cs is retained with a biological half-life of about 500 days. 137 Cs follows the movement of potassium and is excreted into the intestine, reabsorbed from the gastrointestinal (GI) tract into the blood, then to the bile, where it is excreted again into the GI tract by bile via enterohepatic circulation. Without Radiogardase treatment, about 80% of 137 Cs is excreted through the kidneys and about 20% in the feces.

Thallium-201 ( 201 Tl)
Radioactive thallium ( 201 Tl) has a physical half-life of 3 days with electron and photon emissions with a gamma energy peak at 167.4 keV. Non-radioactive thallium has a biological half-life of

8 – 10 days.The physiologic transport of thallium follows the same route as potasium and is excreted by bile in enterohepatic circulation. Without Radiogardase treatment, the fecal to urine excretion ratio of thallium is approximately 2:1.

The results of fecal analysis from patients contaminated with 137 Cs and treated with Radiogardase showed higher activities of 137 Cs in feces, and the associated whole body radioactivity counts showed a more rapid rate of elimination from the body. The effectiveness of Radiogardase for one patient is shown in Figure 1. The whole body content of radioactive material of 137 Cs in kilo-Bequerels (kBq) is shown on the y-axis. Time in days is on the x-axis. Line “A” represents the whole body activity of 137 Cs during prussian blue insoluble treatment at 10 g/day. The dotted line represents extrapolation of the whole body activity if treatment was continued. Line “B” represents the whole body activity of 137 Cs, after prussian blue insoluble was stopped.

Figure 1 : Comparisons of 137Cs whole body activity during and after Radiogardase treatment.
(click image for full-size original)

12.3 Pharmacokinetics

Absorption/Elimination:
Prussian blue insoluble is not absorbed through the intact gastrointestinal wall. Its clearance from the body depends on the gastrointestinal tract transit time.

Food Effects:
Food effect studies have not been conducted. In animal studies, Prussian blue insoluble was not significantly absorbed. Food may increase the effectiveness of prussian blue insoluble by stimulating bile secretion.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been performed to evaluate the carcinogenic or mutagenic potential of prussian blue insoluble. No study on impairment of male or female fertility and reproductive performance has been conducted in animals.

13.2 Animal Toxicology and/or Pharmacology

Absorption/Elimination
In an animal study (pigs, n =38), after a single dose of 40 mg of labeled prussian blue insoluble, 99% of the administered prussian blue dose was excreted unchanged in feces. Absorption from multiple doses has not been studied.

In a study using rats (n = 40, mean body weight range of 188 – 219 grams) injected with 137 Cs, a dose response relationship was demonstrated for the amount of radiation elimination with prussian blue insoluble at doses of 1 to 50 mg/day (Table 1). There is little difference in radiation elimination rate between prussian blue insoluble at doses of 50 to 100 mg/day. In Table 1, the % of Injected Radiation Dose Remaining is defined as the percentage of the total injected dose of 137 Cs remaining in the body at 96 hours post administration.

Table 1: Dose Response Relationship in Rats at 96 Hours

Prussian blue insoluble dose (mg/day)

% Injected 137 Cs dose remaining (Range)

Untreated

58.1 (63.3 – 53.4)

1

9.42 (13.2 – 6.72)

10

1.17 (1.64 – 0.84)

50

0.57 (0.80 – 0.41)

100

0.52 (0.73 – 0.37)

In studies of rats, pigs, and dogs that were internally contaminated with cesium and thallium, the presence of the insoluble complexes in the gastrointestinal lumen changed the primary elimination route from the kidney to the feces and increased the rate of elimination of these two contaminants.

14 CLINICAL STUDIES

14.1 Cesium-137 Contamination

In literature reports, 72 people received Radiogardase after exposure to radioactive cesium ( 137 Cs):

  • 46 patients with 137Cs contamination
  • 19 patients 137Cs contamination in other incidents
  • 7 healthy human subjects who voluntarily ingested trace doses of 137Cs

In a 1987 incident in Goiânia, Brazil, 46 patients with heavy internal contamination with 137Cs were treated with Radiogardase (Table 2). Data on the whole body effective half-life of 137Cs, during and after Radiogardase treatment, was completed on 33 of these 46 patients (see Table 2). Radiogardase reduced the mean whole-body effective half-life of 137Cs by 69%, 46%, and 43% in adults, adolescents, and younger children, respectively.

Table 2 shows the decrease in whole body effective half-life of 137Cs in patients during Radiogardase treatment compared to the half-life of 137Cs after Radiogardase discontinuation (after treatment).

Table 2: Cesium-137 Effective Half-life During and After Treatment with Radiogardase

Group

Age

(years)

Radiogardase Dosage

137 Cs Effective Half Life

During Radiogardase Treatment

After Radiogardase Treatment

Adults (n=5)

> 18

10 grams/day

26 ± 6 days

80 ± 15 days

(all 21 adult patients)

Adults (n=10)

6 grams/day

25 ± 15 days

Adults (n=6)

3 grams/day

25 ± 9 days

Adolescents (n=5)

12 -14

< 10 grams/day

30 ± 12 days

62 ± 14 days

Children (n=7)

4 – 9

< 3 grams/day

24 ± 3 days

42 ± 4 days

Data from additional literature articles including 19 patients contaminated with 137 Cs in other incidents and a study of 7 human subjects who voluntarily ingested trace doses of 137 Cs showed a similar reduction in whole body effective half-life with Radiogardase treatment.

14.2 Thallium Contamination

Thirty-four patients treated with Radiogardase for non-radioactive thallium poisoning have been reported in the literature. Radiogardase treatment reduced the mean serum biologic half-life of thallium from 8 days to 3 days.

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