A44: Antidotes in Depth

Pentetate zinc trisodium and pentetate calcium trisodium (zinc or calcium diethylenetriaminepentaacetate; Zn-DTPA and Ca-DTPA, respectively) are chelators for certain heavy metals and radionuclides. They are approved for the treatment of internal contamination with plutonium, americium, and curium that may occur following unintentional exposure to these metals or following exposure resulting from a radiation dispersal device or “dirty bomb.”

First synthesized in 1954, these chelators were used investigationally to enhance elimination of transuranic elements (Chap. 12).³ DTPA has been used for the extraction of metals from soil and as a treatment for iron overload and lead toxicity.^2,8,21 DTPA and its derivatives have also been used to help with imaging and diagnostics and more recently in chemotherapeutics. Over the last decades, hundreds of human exposures to radionuclides as well as numerous animal studies helped to define the best practices for the use of these chelators, culminating in their approval by the US Food and Drug Administration (FDA) in 2004.

Chemistry

Pentetic acid is a synthetic polyaminopolycarboxylic acid with a molecular weight of 393 Da; the calcium trisodium salt weighs 497 Da, and the zinc trisodium salt weighs 522 Da. It is slightly water soluble and bonds stoichiometrically with a central metal ion through the formal donation of one or more of its electrons.

Related Xenobiotics

Several xenobiotics are used in clinical practice to chelate metals. Among these are deferoxamine, dimercaptol (British anti-Lewisite), dimercapto-propane sulfonate, edetate calcium disodium (ethylenediaminetetraacetic acid), penicillamine, Prussian blue, succimer (dimercaptosuccinic acid), and trientine hydrochloride. However, none of these are effective chelators for transuranic (elements with atomic numbers > 92) metals.

DTPA is used to convey gadolinium contrast in magnetic resonance imaging and technetium in nuclear medicine imaging. Other xenobiotics have modified the DTPA molecule in conjunction with a monoclonal antibody directed toward specific antigens found on neoplasms, allowing an attached isotope, such as ¹¹¹In, to deliver site directed radiation treatment. These related xenobiotics include tiuxetan, pendetide, and pentetreotide.¹⁷

Mechanism of Action

The conjugate base of pentetic acid has a high affinity for metal cations. Pentetic acid wraps itself around the metal forming up to eight bonds, exchanging its calcium or zinc ions for a metal with greater binding capacity (Fig. A44–1). Remaining water soluble, the chelated complex is then excreted by glomerular filtration into the urine. DTPA has specific stability constants for the various elements that it chelates, which presumably explains the different binding efficacies of the calcium and zinc salts.

Pharmacokinetics

DTPA is rapidly absorbed via intramuscular, intraperitoneal, and intravenous routes, but animal studies indicate that DTPA is poorly (< 5%) absorbed by the gastrointestinal tract. Absorption via the lungs is about 20% to 30%. Its volume of distribution is small (0.14 L/kg in humans) and it is distributed throughout the extracellular space. It does not penetrate erythrocytes or other cells such as bone. The plasma half-life is 20 to 60 minutes, although a small fraction is bound to plasma proteins with a half-life of more than 20 hours. DTPA undergoes minimal, if any, metabolism. Only a minimal release of acetate has been demonstrated, and splitting of ethylene groups has not been detected. Elimination is via glomerular filtration, with more than 95% excreted within 12 hours, and 99% by 24 hours. While there are no specific data regarding dosing or clearance changes when chelating patients with kidney disease, individuals with kidney disease who receive ^99mTc-DTPA or Gd-DTPA for imaging purposes demonstrate an increased elimination rate of these chelates with hemodialysis. This suggests that hemodialysis might augment transuranic chelate elimination in contaminated patients with kidney disease.^12,22 Fecal excretion is less than 3%.

Pharmacodynamics

DTPA increases the urinary elimination rate of certain chelated metals. Animal data show that when treatment is begun within an hour of internal contamination, Ca-DTPA resulted in 10 fold greater rate of urinary elimination of plutonium as compared with Zn-DTPA. The greatest chelating capacity occurred immediately and for the first 24 hours following contamination while the metal was still circulating and available for chelation. Following the initial dose of Ca-DTPA, similar rates of elimination of radionuclide resulted from subsequent treatment with either Ca-DTPA or Zn-DTPA, although continued treatment with Ca-DTPA was associated with much greater toxicity, as described in adverse effects below. Animal studies showed that inhalational Ca-DTPA followed by a month-long regimen of Zn-DTPA reduced lung deposits of aerosolized plutonium to 2% of that compared with untreated animals.¹⁸

DTPA is indicated and FDA approved for suspected contamination via inhalation, dermal, or wound exposure from plutonium, americium, and curium, with the goal of mitigating radionuclide incorporation and local tissue irradiation. Inhaled metals, such as might be experienced following an explosion, may be treated with nebulized DTPA. Depending on the chemistry of the metal (eg, uranium concentrates in renal tissue), this irradiation could possibly lead to development of a malignancy later in life. Chelation is indicated to increase elimination of the radionuclide and decrease cancer risk. This latter has only been demonstrated in animals. Increased urinary excretion of transuranic elements is a clinically meaningful endpoint for efficacy of DTPA. Administration of these chelators is not recommended following ingestion of americium, curium, or plutonium, because they will increase gastrointestinal absorption.

A report published by the Radiation Emergency Assistance Center/Training Site (REAC/TS) reviewed data from 685 transuranic element exposures, most of which were plutonium, curium, and americium. Most of these exposures (63.5%) were by inhalation, typically a breach of a confined area where workers access the radioactive material via arm-length gloves reaching into a protective box. Ages of the exposed ranged from 10 to 64 years of age. From the 18 patients with the most complete urine bioassay data, the average increase in urine elimination of radionuclide was 39 times the baseline rate after the first dose of DTPA.¹⁸ By 24 hours, postexposure soluble plutonium and americium are deposited in bone, theoretically rendering DTPA ineffective (in the absence of bone remodeling).⁷ Historic data concerning contaminated workers at nuclear materials production facilities, which included those who received both prolonged and delayed treatments, demonstrated greatly increased urinary excretion of radioactive material.^{1,9, 10, and 11,19,20}

Other more limited data suggest that DTPA may also be effective in increasing urinary elimination following exposure to californium and berkelium, and some experts recommend DTPA for chelation of these elements. Animal data suggest the potential utility for chelating cobalt, einsteinium, lanthanum, nickel, promethium, scandium, strontium, ytterbium, and yttrium. Pentetic acid salts are not effective in removing antimony, beryllium, bismuth, gallium, lead, mercury, neptunium, niobium, platinum, thorium, or uranium.

DTPA is neither recommended nor approved for treating patients contaminated with uranium or neptunium for several reasons. DTPA mobilizes uranium from tissue stores but does not increase urinary elimination.^5,14 Chelating incorporated neptunium is problematic because it forms very stable complexes with transferrin, making it very difficult to decorporate.^6,13

A review of the clinical data by REAC/TS reported three deaths in patients with severe hemochromatosis who were treated with up to 4 g of Ca-DTPA per day. Three other patients experienced severe symptoms with similar dosing, including obtundation and lethargy, oral mucosal ulceration, stomatitis, dermatitis, and loss of lower extremity sensation. These reactions resolved upon cessation of Ca-DTPA administration. Injury was attributed to zinc depletion-induced impaired DNA synthesis in organs with rapid cell turnover.¹⁸ Caution is advised when treating individuals with severe hemochromatosis.

No serious toxicity has been reported among humans after more than 4500 Ca-DTPA administrations at recommended doses.³ Reported adverse reactions include nausea, vomiting, diarrhea, chills, fever, pruritus, and muscle cramps. Transient anosmia was observed in one individual after repeated treatments with Ca-DTPA, also possibly related to zinc depletion, although the specific mechanisms for these adverse reactions remain undefined.

Mice administered 60 times the recommended dose of Ca-DTPA developed severe injuries to kidneys, liver, and the intestines, and deaths occurred.⁵ Toxicity was correlated to the total dose and dosing schedule. Fractionated doses increased mortality compared to similar doses given as a single injection. The injuries were believed to result from significant depletion of Zn and Mn, since the same toxicity did not occur when Zn-DTPA was given at the same dose and schedule. These mice data were interpreted to suggest that Zn-DTPA is approximately 30 fold less toxic than Ca-DTPA. Acutely lethal doses of Zn-DTPA were estimated to be 10 g/kg in the adult male mouse.

Safety

Due to the renal excretion of the radioactive chelate, the kidneys are exposed to potentially higher doses of radiation than other organs, which theoretically may lead to increased risk of malignancy. Additionally, because urine is radioactive during chelation there are recommendations to use toilets instead of urinals and to flush several times. Any spilled urine or feces should be cleaned promptly and completely, accompanied by thorough hand washing. Patients being chelated should take special care to dispose of any expectorant or breast milk carefully. After nebulization treatments, patients should be cautioned not to swallow any expectorant. Nebulized treatment is associated with asthma exacerbations.

If the contamination route is mixed or unknown, then Ca-DTPA should be administered intravenously. The intravenous dose of Ca-DTPA is 1 g in adults and 14 mg/kg up to the adult dose in children under 12 years up to a maximum of 1 g, administered either undiluted over 3 to 4 minutes, or diluted in 100 to 250 mL D₅W, Ringer lactate, or 0.9% sodium chloride, over 30 minutes. On the basis of animal studies, it should not be given more slowly.⁴ Maintaining normal volume status and frequent voiding should be encouraged to dilute the radioactive chelate and minimize exposure to the bladder. If contamination occurred only via inhalation, then Zn-DTPA may be diluted 1:1 with sterile water or 0.9% sodium chloride and administered via nebulization.¹⁶

Although Ca-DTPA is recommended as the initial chelator, Zn-DTPA should be used after the first 24 hours. Although animal studies show a 10 fold increased rate of elimination of Pu with Ca-DTPA compared with Zn-DTPA, trace metals, such as zinc, are excessively removed with continued treatment with Ca-DTPA. After this period, Zn-DTPA given daily at the same dose is recommended for any continuing therapy because of its relatively diminished depletion of trace metals and the absence of liver, kidney, and intestinal injury.

Timing of Administration and Duration of Therapy

Administration of DTPA is recommended to begin as soon as possible, preferably within the first hour following contamination. Historically, about 55% of all patients treated with DTPA required only one dose. The decision to continue therapy should be based on radioassay data. This assessment should include collection of 24-hour urine samples, whole body or chest counting, and close consultation with the hospital radiation safety officer. Assistance is also available from REAC/TS at 865-576–1005; ask for REAC/TS. Current recommendations are to continue chelation until the deposition of contaminant is less than 5% of the maximum permissible body ­burden for a given contaminant.³

If continued therapy is indicated, then a regimen of Zn-DTPA may begin the day following initiation of therapy. Dosing regimens may include Zn-DTPA 1 g intravenously daily up to 5 days per week for the first week. If continuing chelation therapy is indicated, then a twice a week regimen should be initiated until the excretion rate of the contaminant does not increase with Zn-DTPA administration.^15,16 As with the decision to initiate DTPA therapy, any continued treatment must be coordinated with a radiation safety officer. For all patients, data regarding vital signs, adverse effects, and bioassay studies should be reported to the drug manufacturer and also to REAC/TS.

Monitoring

A complete blood count with differential, blood urea nitrogen, serum chemistries and electrolytes, urinalysis, as well as blood and urine radioassays should be obtained prior to initiating treatment. Daily zinc, manganese, and magnesium monitoring should occur as well as supplementation with zinc. During treatment, repeated blood, urine, and fecal radioassays should be run to monitor elimination.

Patients with Chronic Kidney Disease

Although dose adjustment is currently recommended for patients with chronic kidney disease, kidney disease will impair chelate elimination from the body. Hemodialysis might be used to increase the rate of chelate elimination in these patients. Since dialyzed radionuclides will contaminate dialysis fluid, care must be exercised during the procedure as well as in discarding fluid and preparing the machine for subsequent patient use. Consultation with the radiation safety officer (RSO) is recommended to assist with discarding waste material, as well as with the overall chelation treatment of the contaminated patient.

Ca-DTPA is listed as FDA pregnancy category C based on animal data. Mouse studies involving doses up to 10 times the recommended dose for Ca-DTPA did not produce harmful effects, but doses of greater than 20 times the recommended dose produced teratogenicity and fetal death. Zn-DTPA is listed as FDA pregnancy category B, also based on mouse data. Doses up to 31 times the recommended dose were not demonstrated to impair fertility or harm to the fetus. There are no human pregnancy outcome data from which to draw conclusions regarding the risk of DTPA. Contaminated pregnant women are recommended to begin any treatment with Zn-DTPA due to perceived risk for adverse reproductive outcome. However, for pregnant patients with severe internal contamination where the risk to mother and fetus is considered to be high, Ca-DTPA may be considered for a first dose in conjunction with mineral supplements that contain zinc. These chelators do not cross the placental barrier.

There are no studies regarding DTPA excretion in breast milk. However, radiocontaminants are excreted in breast milk. Thus, women with known or suspected contamination should not breast feed. Likewise, there are no data regarding safety in lactating women, and data regarding the use in children are extrapolated.

DTPA is available as Ca-DTPA or Zn-DTPA as a sterile solution in 5 mL ampules containing 200 mg/mL (1 g per ampule) for intravenous use. It should be stored in a cool, dry place with an ambient temperature of between 59°F (15°C) and 86°F (30°C) away from sunlight. Several manufacturers formulate DTPA for intravenous administration. Five mL ampules are available singly and in 10 packs. Both chelators are maintained in the Strategic National Stockpile.

• DTPA is a safe and effective means of chelating americium, curium, and plutonium in a contaminated patient.

• Rapid consultation with a radiation safety officer is recommended to determine the type and degree of contamination, as well as the need and duration of any treatment.

• In most cases, Ca-DTPA should be started as soon as possible after a contamination followed by the use of Zn-DTPA if continued treatment is needed.

• Regular monitoring and supplementation of zinc, magnesium, and manganese during therapy is recommended, although the risk of clinically significant depletion is low at therapeutic doses.

• Hemodialysis may be used to increase renal elimination when chelating contaminated patients with kidney disease, although specific data for this use are limited.

References