A26: Antidotes in Depth

Succimer (meso-2,3-dimercaptosuccinic acid, DMSA) is an orally active metal chelator that is approved by the US Food and Drug Administration (FDA) for the treatment of lead poisoning in children with blood lead concentrations higher than 45 µg/dL. Succimer is also used to treat patients poisoned with arsenic and organic and inorganic mercury. Succimer has a wider therapeutic index and exhibits many advantages over dimercaprol and edetate calcium disodium (CaNa₂EDTA), the two other chelators used for the same clinical problems. Animal studies suggest that succimer does not redistribute lead or arsenic to the central nervous system. The role of succimer alone and in conjunction with other chelators to treat lead encephalopathy continues to be defined.^60,73

Succimer was initially synthesized in 1949 in England.⁷¹ In 1954, antimony-a,a′-dimercaptopotassium succinate (TWSb) was developed to treat schistosomiasis.⁴² TWSb is antimony bound to the potassium salt of succimer in a 2:3 ratio, forming a water-soluble xenobiotic with 50 times less toxicity than the previously used antimony compound, tartar emetic. Several years later, a group from Shanghai demonstrated the ability of the sodium salt of succimer to increase the LD₅₀ of tartar emetic 16-fold in mice.¹⁰⁹ An early review of the Chinese experience with intravenous (IV) succimer in the treatment of occupational lead and mercury poisoning suggested efficacy similar to IV CaNa₂EDTA in increasing urinary lead and to intramuscular (IM) DMPS (racemic-2,3-dimercapto-1-propanesulfonic acid, unithiol) for mercury, with little observed toxicity.¹⁰⁵ This experience, the subsequent widespread use in Asia^{75,78,90,105,106,112} and Europe,^{17,34,40,43,63,99} and the realization that succimer could be used orally,^7,49 led to US-based animal experiments, human trials, and FDA approval in 1991 for the treatment of lead-poisoned children.

Chemistry

Succimer is a white crystalline powder with a molecular weight of 182 Da and a characteristic sulfur odor and taste.⁶ Succimer is the meso form of 2,3-dimercaptosuccinic acid. It is highly polar and water soluble.

Related Agents

DMPS (racemic-2,3-dimercapto-1-propanesulfonic acid, Na salt) is a chelator that, like succimer, is a water-soluble analog of British anti-Lewisite (BAL).^7,9,23 A dose of 15 mg/kg of DMPS is equimolar to 12 mg/kg of succimer. DMPS has been used in the Soviet Union since the late 1950s and continues to be used in Russia and other former Soviet countries. DMPS, which is an investigational drug in the United States, is marketed in both oral and parenteral forms in Germany as Dimaval. DMPS seems promising in mercury and arsenic poisoning.^{3,5,7,9,11,14,23,45} DMPS is associated with an increase in the urinary excretion of copper and the development of Stevens-Johnson syndrome.^26,104 Like succimer, DMPS does not appear to redistribute mercury or lead to the brain. Additional research is needed to determine whether DMPS is more advantageous than succimer, given its lower LD₅₀ in mice (5.22 mmol/kg versus 13.58 mmol/kg for succimer) when administered intraperitonealy.

Mechanisms of Action

Succimer contains four ionizable hydrogen ions, giving it four different pK_as—2.31, 3.69, 9.68, and 11.14—with the dissociation of the two lower values representing the carboxyl groups and the two higher values the sulfur groups.⁴ Lead and cadmium bind to the adjoining sulfur and oxygen atoms, whereas arsenic and mercury bind to the two sulfur moieties, forming pH-dependent water-soluble complexes (Fig. A26–1).⁸⁵

Pharmacokinetics and Pharmacodynamics

Succimer is highly protein bound to albumin through a disulfide bond. Subhuman primate studies of IV and oral ²²C succimer indicate that following an IV dose, radiolabelled succimer is eliminated almost exclusively via the kidney, with only trace amounts (< 1%) excreted via feces or expired air.⁷¹ Following the administration of a single oral dose of 10 mg/kg, succimer is rapidly and extensively metabolized.⁶⁸ Approximately 20% of the administered oral dose is recovered in the urine, presumably reflecting the low bioavailability of the drug.¹⁰ Of the total drug eliminated in the urine (20%), 89% is altered and in the form of disulfides of L-cysteine. The majority of the altered succimer is in the form of a mixed disulfide with two molecules of L-cysteine to one molecule of succimer.⁸ The remaining 11% is excreted as unaltered free succimer.⁶⁸ Maximal excretion of succimer occurs in urine specimens collected between 2 and 4 hours after administration. Surprisingly, the blood only contains albumin-bound succimer and no evidence of the altered disulfide moieties, which suggests that the kidney may be involved in the biotransformation of succimer. It is likely that succimer gains entry to the kidney via an active organic anion transporter.^21,111

The pharmacokinetics of a single oral dose of succimer were determined in three children and three adults with lead poisoning and in five healthy adult volunteers.³³ Children received 350 mg/m² of succimer and adults received 10 mg/kg of succimer. The peak concentration and the time to peak blood concentration of total succimer (parent vs. altered oxidized metabolites) were similar for all three groups. The half-life of total succimer was 1.5 times longer in the children than in either adult group. The renal clearance of total succimer was greater in healthy adults (CrCl 77 mL/min) than in lead-poisoned adults (CrCl 25 mL/min) and children (CrCl 17 mL/min) with reduced creatinine clearances. Distribution of succimer (parent and/or oxidized metabolites) into erythrocytes appeared greater in poisoned patients than in the healthy adults.³³

The metabolism of succimer was studied in lead-poisoned children and in normal adults.¹⁵ The results indicate that succimer undergoes an enterohepatic circulation facilitated by gastrointestinal (GI) microflora. Similar to the previous pharmacokinetic study, moderate lead exposure impaired the renal elimination of succimer.

In addition to precise analysis of metal elimination kinetics, measures of clinical outcome are essential for an understanding of the utility of this chelator. The Treatment of Lead-Exposed Children (TLC) trial was a step in that direction.¹⁰² The TLC trial was a randomized, multicenter, double-blind, placebo-controlled study to examine the effects of succimer on cognitive development, behavior, stature, and blood pressure in children 1 to 3 years of age with blood lead concentrations between 20 and 44 µg/dL and 780 children were enrolled.⁸⁶ The children received up to three courses of 26 days each of succimer compared to placebo. For the first 7 days the children received 350 mg/m² three times a day and for the remaining 19 days they received 350 mg/m² twice a day. The largest drop in blood lead occurred within the first week of therapy with succimer and then rebounded somewhat. This pattern was repeated with repeated courses. However, at the end of one year, no difference was seen in the blood lead concentrations between the succimer and the placebo groups. There was also no difference in test scores on cognition, behavior, or neuropsychological function.⁸⁶ A follow-up study conducted on those children at age 7 confirmed the lack of benefit in chelating children with succimer whose blood lead concentrations were 20 to 44 μg/dL, at ages 1 to 3 years.³⁵ A case study showed similar results. Similarly, succimer showed no benefit on growth in children aged 12 to 33 months with blood lead concentrations of 20 to 44 µg/dL.⁸²

Several groups are studying the efficacy of succimer in reducing blood, brain, and tissue lead by using rat and nonhuman primate models of childhood and adult lead poisoning.^91,92,94 Although monkeys most closely resemble humans in their lead-associated toxicity, using them in studies is costly⁷⁷; the rat model is economical but limited because of species differences in lead and succimer metabolism and efficacy.

The validity of using blood lead concentrations as a marker of brain lead was studied in the adult rhesus monkey. Lead was administered orally for 5 weeks to achieve a target blood lead concentration of 35 to 40 µg/dL.³² Five days after the cessation of lead exposure, succimer chelation was initiated in the currently approved dosage regimen. Two IV doses of radioactive lead tracer were administered prior to succimer chelation to study the kinetics of recent versus chronic lead uptake and distribution. Four areas of the brain, as well as blood and bone, were assayed for lead. Merely stopping further lead exposure significantly reduced blood lead concentrations by 63% and brain lead concentrations by 34% compared with pretreatment concentrations, a finding that was not statistically different from succimer administration after halting exposure. However, when an integrated area under the serum lead concentration versus time curve (AUC) blood analysis was used over the 19-day succimer treatment course, instead of a single blood lead concentration, the differences between succimer and control were statistically significant. The clinical significance of these differences is unclear. Succimer-treated animals showed the greatest drop in blood lead concentrations over the first 5 days, while a similar end point was gradually achieved in the control. The lead from both the recent exposure (radioactive tracer lead) and chronic exposure declined to the same extent, independent of treatment with succimer. A better correlation was found between brain prefrontal cortex lead concentrations and an integrated blood lead analysis than with a single blood lead measurement.

Similarly, a study in neonatal rats demonstrated that increasing the duration of succimer chelation from 7 to 21 days decreased brain lead concentrations without a corresponding decrease in blood lead concentrations.⁹¹ The authors proposed that a slow rate of egress of brain lead to the blood was responsible for the demonstrable benefit of prolonging therapy to 21 days. In this study, succimer decreased blood lead concentration by approximately 50% when compared with the vehicle as the control, and this difference persisted for the 21 days of treatment. With succimer treatment, brain lead concentration decreased by 38% at 7 days and by 68% at 21 days. This same group also demonstrated that rats exposed to lead from postnatal days 1 to 30, then treated with succimer, demonstrated reductions in blood and brain lead concentrations and an improvement in cognitive deficits.⁹⁵ Previous animal studies demonstrated the ability of succimer to enhance urinary lead elimination^41,49,94 and to reduce blood,^{16,30,38,39,54,80,92,94,96,98} brain,^{16,30,80,97,98} liver,⁹⁴ and kidney lead concentrations,^{16,30,38,54,80,98} while either reducing^16,54,80,98 or demonstrating no effect on bone lead concentrations.^30,94 These studies differ in the amounts and duration of lead administration prior to chelation, as well as in route, dose, and duration of chelation; however, several months after a course of succimer chelation, tissue lead concentrations had returned to concentrations found in the pretreatment stage.³⁰ Given the limited absolute amount of lead that is actually eliminated by chelation in comparison to the total body burden, particularly bone, these transient effects are not surprising.

Under a variety of experimental conditions in animals, succimer prevents the deleterious effect of lead on heme synthesis,^16,49,80 blood pressure,⁵⁸ and behavior.⁹⁶

The use of succimer in both children and adults with chronic lead poisoning demonstrated consistent findings.^{18,27,50, 51, and 52,64,76} During the first 5 days of succimer chelation (1050 mg/m²/d in children, 30 mg/kg/d in adults both in three divided doses), the blood lead concentration dropped precipitously by approximately 60% to 70%. This blood lead concentration remained unchanged during the next 14 to 23 days of continued therapy. Increases in urinary lead excretion are concurrent with the drop in blood lead concentration, with maximal excretion occurring on day 1.^27,51 Urinary lead excretion exceeds estimated blood content which suggests that some lead is being removed from soft tissues as a concentration gradient is established from tissue to blood to urine.^27,52 Typically, 2 weeks after the completion of succimer, blood lead concentration rebounds to values 20% to 40% lower than pretreatment values. In the one randomized, double-blind, placebo-controlled trial of succimer use in children with pretreatment blood lead concentrations of 30 to 45 µg/dL, follow-up at 1 month and at 6 months showed no differences between succimer-treated children and controls.⁷⁶ Succimer restores red blood cell D-aminolevulinic acid dehydratase activity, decreases erythrocyte protoporphyrin, and decreases urinary excretion of D-aminolevulinic acid and coproporphyrin.^{18,27,51,52,76}

There is a large body of evidence reporting on the usage and safety profile of succimer in adults with chronic lead poisoning.^{13,17,27,40,43,44,47,48,59,61,69,83,100,103} The published experience outside the United States with the use of oral succimer for metal poisoning includes nearly 100 adult cases and contributes considerably to the supporting evidence. At least 74 additional individuals have been successfully treated parenterally (IM or IV) with the sodium salt of succimer.^13,17,40,43

The experience with the use of succimer in severely lead-poisoned patients, including those with encephalopathy, is limited.^40,43,51 Three children with mean blood lead concentrations higher than 70 µg/dL who were treated with 5 days of succimer achieved comparable declines in blood lead concentration to two similar children who had been treated previously with a combination of BAL for 3 days and CaNa₂EDTA for 5 days.⁵¹ Three adult patients with encephalopathy achieved significant improvement following succimer chelation.⁴⁰ A 3 year-old child with a massive lead exposure superimposed on chronic lead poisoning and a blood lead concentration of 550 µg/dL was given BAL and CaNa₂EDTA for 5 days, with whole-bowel irrigation (WBI) performed on the first 3 days and succimer following WBI beginning on day 3 and continuing for 19 days. The blood lead concentration dropped from 550 to 70 µg/dL on day 5, but it rebounded to 99 µg/dL 2 days after BAL and CaNa₂EDTA—but not the succimer—were discontinued.⁴⁶

Succimer has been used for arsenic toxicity in China and the Soviet Union since 1965.^7,13 Animal studies with sodium arsenite and lewisite demonstrate the ability of succimer to improve the LD₅₀ with a good therapeutic index, lack of redistribution of arsenic to the brain as compared to BAL or control, and reduced kidney and liver arsenic concentrations.^{7,13,62,81,87} A few case reports attest to the ability of succimer to enhance the urinary excretion of arsenic^31,88 and after 2 to 7 weeks of chelation urinary arsenic returned to normal concentrations following ingestion of arsenic trioxide ant bait by toddlers.¹⁰⁷ A randomized, placebo-controlled trial of succimer to treat 21 patients with chronic arsenic poisoning in India who had stopped ingesting arsenic contaminated water 5 months previously demonstrated improved clinical results and enhanced urinary excretion of arsenic in both the treatment and placebo groups, but no statistical differences could be demonstrated.⁷⁰ A comparison of BAL, succimer, and DMPS as arsenic antidotes demonstrated higher therapeutic indices for succimer and DMPS over BAL in chronic arsenic poisoning.⁷⁴

Succimer enhances the elimination of mercury and has been used to treat patients poisoned with inorganic, elemental, and methylmercury. It improves survival, decreases kidney damage, and enhances the elimination of mercury in animals following exposure to inorganic mercury^{4,22,54,57,65,84,110} and methylmercury.^1,2,9,66 However, one study in mice subjected to intraperitoneal mercuric chloride demonstrated an enhanced deposition of mercury in motor neurons following chelation with succimer or DMPS.³⁷ Of 53 construction workers who were exposed to mercury vapor, 11 received succimer and N-acetyl-d,l-penicillamine in a crossover study.²⁰ Mercury elimination was increased during the period of succimer administration compared with the period of N-acetyl-d,l-penicillamine administration. Because the chelators were administered for only 2 weeks and late in the clinical course, therapeutic benefit could not be evaluated. When succimer was given to victims of an extensive Iraqi methylmercury exposure, blood methylmercury half-life decreased from 63 days to 10 days.⁷

Succimer is generally well tolerated with few serious adverse events reported.^27,28,86,101 Common adverse events are typically GI in nature, including nausea, vomiting, flatus, diarrhea, and a metallic taste in 10% to 20% of patients. Rashes have been reported in about 4% of patients.²⁴ Some of these required discontinuation of the succimer. Mild elevations in aspartate aminotransferase and alanine aminotransferase are reported.^{21,26,28,52,64,79,111} Rarely, chills, fever, urticaria, reversible neutropenia, and eosinophilia are reported.^18,27,28,47 Because neutropenia has been observed in some patients taking succimer and because bone marrow effects have been reported with other drugs in the same chemical class, the manufacturer’s package insert recommends a complete blood count with a differential and a platelet count before and weekly during treatment.²⁴ During the latest open-label prospective study in children, apparently unrelated adverse events included an elevation in bone-derived alkaline phosphatase, eosinophils, and elevated serum aminotransferases.²⁷ One patient developed severe hyperthermia and hypotension reportedly related to succimer administration.⁷⁹

The Chinese have reported a high incidence of more serious adverse effects (including dizziness and weakness) in response to IV or IM succimer.^106,112 This discrepancy is undoubtedly related to the substantially greater dose of succimer delivered from parenteral administration compared with the relatively low (approximately 20%)⁷¹ oral bioavailability of succimer as a result of first-pass metabolism.

Incidental chelation of essential elements is always a concern with the use of chelators. A number of studies using succimer demonstrate no rise in urinary zinc, copper, iron, or calcium.^{27,40,43,50, 51, and 52} Urinary excretion of essential elements was the focus of a study in a primate model of childhood lead exposure.⁹² Infant rhesus monkeys were exposed to lead for the first year of life to achieve blood lead concentrations of 40 to 50 µg/dL. Succimer was administered in the standard dosage regimen and complete urine collections over the first 5 days were analyzed for calcium, cobalt, copper, iron, magnesium, manganese, nickel, and zinc. Only when the data were analyzed collectively for all eight elements on all 5 days was there a statistically significant increased urinary elimination. These results raise concern that children subjected to repeated succimer chelation may also be at risk for enhanced elimination of essential elements.^27,92,94 Therefore, children should be monitored and repleted as necessary. There is still relatively limited clinical experience with the xenobiotic, particularly with regard to long-term administration.

One concern with administering succimer orally is that outpatient management might permit continued unintentional lead exposure and the possibility for succimer-facilitated lead absorption. Studies with d-penicillamine, dimercaprol,⁵⁵ and CaNa₂EDTA demonstrate enhanced lead absorption and elevated blood lead concentrations.

Most blood lead concentrations are measured by graphite furnace atomic absorption spectrophotometry, in which case succimer does not interfere with the measurement. However, if blood lead concentrations were to be measured by anodic stripping voltammetry, succimer would affect the results by chelating the mercury in the electrode.²⁴ Succimer may cause a false-positive result for urinary ketones when tests using nitroprusside reagents (eg, Ketostix) are used, and a falsely decreased serum uric acid and creatine phosphokinase concentrations may been seen.²⁴

Animal studies suggest that succimer does not promote lead reten­tion in the setting of continued exposure unless lead exposure is over­whelming.^49,56,80 A radiolabeled lead tracer administered to adult volunteers suggested that succimer increased the net absorption of lead from the GI tract and may have distributed it to other tissues, as well as having enhanced urinary elimination.⁹³ Absorption is bimodal and consistent with an initial phase, followed by a delayed increase attributable to an enterohepatic effect. It may be that succimer-enhanced urinary lead elimination often exceeds enhanced lead absorption.⁸¹ One study reported two children with environmental exposure and dramatic rises in blood lead concentration while receiving succimer.²⁷ In the event of exposure to a new lead source, decontamination of the GI tract should complement oral succimer.⁷²

Although iron supplementation cannot be given concomitantly with BAL, because the BAL–iron complex may be a potent emetic, iron has been given concomitantly to patients receiving oral succimer without any adverse events.⁵³ The prevalence of both iron deficiency and elevated blood lead concentrations is highest among poor, inner-city children.⁶⁷ Because heme is a constituent of all cells, including those of the brain, it appears clinically indicated to provide iron supplementation during chelation therapy, when the heme pathway is freed of the inhibitory effects of lead. The timing of administration of the iron should be separate from administration of the succimer.²⁷

A case report describes a 3 year-old child who reportedly ingested 185 mg/kg of succimer and was asymptomatic.⁸⁹

Succimer is FDA pregnancy category C. There are no adequate studies in pregnant women. The use of succimer in pregnancy is restricted to women who warrant therapy based on their symptoms.²⁷ There was a dose-dependent effect of succimer on early and late fetal resorption and on fetal body weight and length when succimer was administered to pregnant mice during organogenesis. No observed teratogenic effects were noted when 410 mg/kg, or approximately 5% of the acute LD₅₀, of succimer was administered subcutaneously.³⁶ However, doses of 410 to 1640 mg/kg/d of succimer administered subcutaneously to pregnant mice during organogenesis are teratogenic and fetotoxic, and doses of more than 510 mg/kg/d to pregnant rats also showed problems with reflexes in the offspring.²⁴ Succimer 30 to 60 mg/kg/d was administered by gavage to lead-poisoned rats from days 6 to 21 of gestation.²⁵ These doses of succimer decreased embryonic and fetal blood lead concentrations and normalized offspring body weight at 13 weeks. Although succimer was able to reverse some lead-induced immunotoxic effects, succimer itself caused problems with the immune system that persisted into adulthood.²⁵ Female mice exposed to lead in utero and then administered succimer from the fourth day of gestation to parturition demonstrated decreased blood lead concentrations; however, fetal liver and bone concentrations increased and worsened neural development in the offspring.¹⁰⁸ The use of succimer during pregnancy should only be undertaken if the potential benefit justifies the potential risk to the fetus.²⁴

Succimer can be combined with CaNa₂EDTA to take advantage of the ability of succimer to remove lead from soft tissues, including the brain, while capitalizing on the ability of CaNa₂EDTA to mobilize lead from bone.³⁰ A number of rodent models have examined this combination and found it to be superior in enhancing the elimination of lead, in reducing tissue concentrations of lead, and in restoring some lead-induced biochemical abnormalities.^38,39,97 Although the addition of succimer to CaNa₂EDTA prevented the redistribution of lead to the brain caused by CaNa₂EDTA alone, the combination also increased urinary excretion of zinc, calcium, and iron.^97,98 A retrospective review comparing dimercaprol plus CaNa₂EDTA to succimer plus CaNa₂EDTA in children with blood lead concentrations greater than 45 µg/mL, demonstrated a similar reduction in blood lead concentrations at the end of treatment and at 14 and 33 days following the termination of treatment.¹⁹ Blood lead concentration reductions were approximately 75%, 40%, and 37% at the end of therapy and at 14 and 33 days posttreatment, respectively. The succimer plus CaNa₂EDTA combination was better tolerated.

The dosage is 350 mg/m² in children, three times a day for 5 days, followed by 350 mg/m² twice a day for 14 days. In adults, the dosage is 10 mg/kg three times a day for 5 days followed by 10 mg/kg twice a day for 14 days. At approximately 5 years of age, dosing based on body surface area approximates the 10 mg/kg dose, while for children younger than 5 years of age dosing by body surface area, as was done during the premarketing trials, gives higher doses and is recommended.^29,73 Repeated courses may be needed depending on the blood lead concentration. However a minimum of 2 weeks between courses is recommended unless blood lead concentrations mandate otherwise.²⁴ For patients who cannot swallow the capsule whole, it can be separated immediately prior to use and the contents sprinkled into a small amount of juice or on apple sauce, ice cream, or any soft food, or placed on a spoon and followed by a fruit drink (Table A26–1).

Succimer (Chemet) is available as 100-mg bead-filled capsules.

• Succimer (meso-2,3-dimercaptosuccinic acid) is an orally active metal chelator that is FDA approved for the treatment of lead poisoning in children with blood lead concentrations higher than 45 µg/dL.

• There is no evidence at this time that succimer improves cognitive performance in patients with blood lead concentrations lower than 45 µg/dL.

• Succimer is also used to treat patients poisoned with arsenic and organic and inorganic mercury.

• The advantages of succimer use include oral administration, limited effects on trace metals such as zinc, enhanced patient tolerance, limited toxicity, and the ability to coadminister iron (if needed). It is not contraindicated in glucose-6-phosphate dehydrogenase–deficient individuals.

• By contrast to CaNa₂EDTA, succimer does not redistribute lead to the brain of poisoned animals.^11,30

References