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Ca-DTPA

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Ca-DTPA

CLINICAL PHARMACOLOGY

General

Ca-DTPA (pentetate calcium trisodium inj) forms stable chelates with metal ions by exchanging calcium for a metal of greater binding capacity. The radioactive chelates are then excreted by glomerular filtration into the urine. In animal studies, Ca-DTPA (pentetate calcium trisodium inj) forms less stable chelates with uranium and neptunium in vivo resulting in the deposition of these elements in tissues including the bone. Ca-DTPA (pentetate calcium trisodium inj) treatments are not expected to be effective for uranium and neptunium. Radioactive iodine is not bound by DTPA.

Pharmacodynamics

In a study of rodents internally contaminated with plutonium, the rate of plutonium elimination was measured after treatment with Ca-DTPA (pentetate calcium trisodium inj) and Zn-DTPA given intravenously as a single dose of 10 to 1,000 Ámol/kg (0.54 –54 x maximum human dose, MHD). When treated within one hour of internal contamination, Ca-DTPA (pentetate calcium trisodium inj) resulted in about a 10-fold higher rate of elimination of plutonium in the urine as compared to Zn-DTPA. The chelating capacity of Ca-DTPA (pentetate calcium trisodium inj) is greatest immediately and up to approximately 24 hours after internal contamination when the radiocontaminant is still circulating and readily available for chelation. After the first dose of Ca-DTPA (pentetate calcium trisodium inj) , maintenance treatment with either Ca-DTPA (pentetate calcium trisodium inj) or Zn-DTPA resulted in similar rates of elimination of radioactivity. However, at comparable doses, Ca-DTPA (pentetate calcium trisodium inj) had more toxicity (e.g., more depletion of trace metals, higher rate of mortality, the presence of kidney and liver vacuolization, and small bowel hemorrhagic lesions).

In another study, rodents contaminated with aerosolized plutonium and americium were treated with Ca-DTPA (pentetate calcium trisodium inj) and Zn-DTPA. The treatment schedule involved inhalation of Ca-DTPA (pentetate calcium trisodium inj) 2 Ámol/kg (0.11 MHD) 30 minutes after contamination followed by inhalation of Zn-DTPA 2 Ámol/kg at approximately 6 hours, 1, 2, 3, and 6 days, then twice weekly to day 26 or day 27. The treatment regime reduced the lung deposit of plutonium and americium to 1-2% of that in untreated animals. Systemic deposit in liver and skeleton were reduced by half.

Literature and U.S. Registry data in humans indicate that intravenous administration of Ca-DTPA (pentetate calcium trisodium inj) forms chelates with radioactive contaminants found in the circulation, interstitial fluid, and tissues. When Ca-DTPA (pentetate calcium trisodium inj) is administered by inhalation within 24 hours of internal radioactive contamination, it can chelate transuranium elements. Expectoration is expected to decrease the amount of radioactive contaminant available for systemic absorption.

The effectiveness of chelation decreases with time after internal contamination because the transuranium elements become incorporated into the tissues. Chelation treatment should be given as soon as possible after known or suspected internal contamination with transuranium elements has occurred. (See DOSAGE AND ADMINISTRATION)

Pharmacokinetics

Plasma retention and urinary excretion data were obtained in 2 subjects that received 750 kBq of 14C-DTPA. As shown in Figure 1, the radiolabeled DTPA was rapidly distributed throughout the extracellular fluid space and was cleared by glomerular filtration. The plasma retention up to 7 hours post dosing was expressed by the sum of three exponential components with average half-lives of 1.4 min, 14.5 min, and 94.4 min. The level of activity in the plasma was below the limit of detection 24 hours after injection. During the study, no detectable activity was exhaled or excreted in the feces. By 24 hours, cumulative urinary excretion was more than 99% of the injected dose.

Figure 1: Percent of 14C-DTPA Distribution

Percent of 14C-DTPA Distribution - Illustration

Absorption

Ca-DTPA (pentetate calcium trisodium inj) is poorly absorbed in the GI tract. In animal studies, after oral administration, absorption was approximately 5%. In a U.S. Registry of 18 patients who received a single inhaled or intravenous dose of 1 gram, urine data indicate that the inhaled product was absorbed and resulted in a comparable elimination of the radiocontaminant. One study of 2 human subjects that received Ca-DTPA (pentetate calcium trisodium inj) with 14C-DTPA by inhalation revealed approximately 20% absorption from the lungs. Human or animal bioavailability comparisons for Ca-DTPA (pentetate calcium trisodium inj) are not available after administration by inhalation and intravenous injection. (See CLINICAL PHARMACOLOGY, Clinical Trials)

Distribution

Following intravenous administration, Ca-DTPA (pentetate calcium trisodium inj) is rapidly distributed throughout the extracellular fluid space. No significant amount of Ca-DTPA (pentetate calcium trisodium inj) penetrates into erythrocytes or other cells. No accumulation of Ca-DTPA (pentetate calcium trisodium inj) in specific organs has been observed. There is little or no binding of the chelating agent by the renal parenchyma.

Metabolism

Ca-DTPA (pentetate calcium trisodium inj) undergoes a minimal amount of metabolic change in the body.

Adverse Metabolic Effects: Studies in animals and humans showed that Ca-DTPA (pentetate calcium trisodium inj) binds endogenous metals of the body (i.e., zinc (Zn), magnesium (Mg) and manganese (Mn)). In an animal study, high doses of Ca-DTPA (pentetate calcium trisodium inj) led to the loss of zinc and manganese mainly from the small intestine, skeleton, pancreas, and testes. Dosing over several days resulted in mobilization or binding of endogenous metals in exchange for calcium and a consequent impairment of metal-controlled or activated systems. The rate and amount of endogenous metal depletion increased with split daily dosing and with the length of treatment. Depletion of these endogenous metals can interfere with necessary mitotic cellular processes. Over longer time periods, depletion of zinc due to Ca-DTPA (pentetate calcium trisodium inj) therapy may result in transient inhibition of a metal-loenzyme–aminolevulinic acid dehydrase (ALAD) in the blood and suppressed hematopoiesis.

Elimination

Ca-DTPA (pentetate calcium trisodium inj) is cleared from the plasma in the first few hours after dosing through urinary excretion by glomerular filtration. Renal tubular excretion has not been documented. In stool samples tested, only a very small amount of radioactivity ( < 3%) was detected.

Renal Impaired and/or Compromised Liver Function Patients

Adequate and well-controlled pharmacokinetic and pharmacodynamic studies in renally impaired and/or hepatically impaired patients were not identified in the literature. Both Ca-DTPA (pentetate calcium trisodium inj) and its radioactive chelates are excreted by glomerular filtration. Impaired renal function may decrease their rates of elimination and increase the serum half-life of Ca-DTPA (pentetate calcium trisodium inj) .

Clinical Trials

All clinical data has come from the treatment of individuals who were accidentally contaminated. Observational data were maintained in a U.S. Registry of individuals with internal radioactive contamination primarily from acute occupational contamination with plutonium, americium, and curium.

In 286 individuals, bioassays were available to measure urinary radioactivity elimination after chelation therapy. Of these 286 individuals, 18 had matched pre- and post-chelator urine radioactivity bioassay results available.

Seventeen of these individuals received 1 gram of Ca-DTPA (pentetate calcium trisodium inj) as the first dose. Of these, 9 individuals received the first dose by nebulization (1:1 Ca-DTPA (pentetate calcium trisodium inj) and saline) and 8 received Ca-DTPA (pentetate calcium trisodium inj) intravenously. The elimination of radio-contaminants was measured using the ratio of the urine radioactivity before treatment to the maximum urine radioactivity after treatment (the excretion enhancement factor, EEF). As shown in Table 1, after one dose, the mean EEF was 25.7. The descriptive results and variability for the intravenous, inhaled, and combined routes are considered to be similar.

Table 1 : Urine Excretion Enhancement Factor (EEF) of Transuranium Elements after an Initial Dose of 1g Ca-DTPA (pentetate calcium trisodium inj) , N=17

Results Intravenous Inhaled Combined Routes
Mean 25.9 25.4 25.7
Median 12.5 19.3 12.8
SD 33.8 28.2 30.1
Range 1.1-396.1 0.5-80.0 0.5-396.1

After initial treatment with Ca-DTPA (pentetate calcium trisodium inj) , maintenance treatment was continued with 1 gram Zn-DTPA doses over a period of days, months or years, depending upon the extent of internal contamination and individual response to therapy. Most patients received a single dose of Ca-DTPA (pentetate calcium trisodium inj) . The longest treatment duration was approximately 6.5 years. Similar increases in urinary radioactivity elimination following chelator administration were supported by data from the remaining 268 individuals in the U.S. Registry and from the literature.

Last reviewed on RxList: 1/7/2009
This monograph has been modified to include the generic and brand name in many instances.

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