Chemet Pharmacology, Pharmacokinetics, Studies, Metabolism - Succimer

Chemet Pharmacology, Pharmacokinetics, Studies, Metabolism - Succimer

CLINICAL PHARMACOLOGY

Succimer is a lead chelator; it forms water soluble chelates and, consequently, increases the urinary excretion of lead.

Preclinical Toxicology:   In an ongoing six month chronic oral toxicity study in dogs, thrombocytopenia was observed in animals receiving succimer at 80 or 140 mg/kg/day after three months of dosing. Preliminary gross pathology findings in the affected dogs included ecchymoses in a number of organs. No depressed platelet counts were observed in dogs receiving succimer at 10 mg/kg/day for three months. Platelets were not enumerated in previous oral toxicity studies up to 28 days. In those studies, daily doses of succimer up to 200 mg/kg/day did not produce any significant overt toxicity in rats and dogs. However, six and twenty-eight day oral toxicity studies in dogs have shown that doses of 300 mg/kg/ day or higher were toxic and lethal to some dogs. Kidney and gastrointestinal tract were the major target organs for succimer toxicity. Toxicity was manifested by anorexia, emesis, mucoid and/or bloody diarrhea, increased blood urea nitrogen concentration, increased SGPT, SGOT and alkaline phosphatase levels, renal tubular necrosis, purulent nephritis and severe gastrointestinal bleeding and ulceration. Deaths were due to renal failure.

Pharmacokinetics:   In a study performed in healthy adult volunteers, after a single dose of ¹⁴ C-succimer at 16, 32, or 48 mg/kg, absorption was rapid but variable with peak blood radioactivity levels between one and two hours. On average, 49% of the radiolabeled dose was excreted: 39% in the feces, 9% in the urine and 1% as carbon dioxide from the lungs. Since fecal excretion probably represented non-absorbed drug, most of the absorbed drug was excreted by the kidneys. The apparent elimination half-life of the radio-labeled material in the blood was about two days.

In other studies of healthy adult volunteers receiving a single oral dose of 10 mg/kg, the chemical analysis of succimer and its metabolites in the urine showed that succimer was rapidly and extensively metabolized. Approximately 25% of the administered dose was excreted in the urine with the peak blood level and urinary excretion occurring between two and four hours. Of the total amount of drug eliminated in the urine, approximately 90% was eliminated in altered form as mixed succimer-cysteine disulfides; the remaining 10% was eliminated unchanged. The majority of mixed disulfides consisted of succimer in disulfide linkages with two molecules of L-cysteine, the remaining disulfides contained one L-cysteine per succimer molecule.

Pharmacodynamics:   Dose ranging studies were performed in 18 men with blood lead levels of 44-96 µg/dL. Three groups of 6 patients received either 10.0, 6.7 or 3.3 mg/kg succimer orally every 8 hours for 5 days. After five days the mean blood levels of the three groups decreased 72.5%, 58.3% and 35.5% respectively. The mean urinary lead excretions in the initial 24 hours were 28.6, 18.6 and 12.3 times the pretreatment 24 hour urinary lead excretion. As the chelatable pool was reduced during therapy, urinary lead output decreased. A mean of 19 mg of lead was excreted during a five-day course of 30 mg/kg/day succimer. Clinical symptoms, such as headache and colic and biochemical indices of lead toxicity also improved. Decrease in urinary excretion of d-aminolevulinic acid (ALA) and coproporphyrin paralleled the improvement in erythrocyte d-aminolevulinic acid dehydratase (ALA-D). Three control patients with lead poisoning of similar severity received CaNa ₂ EDTA intravenously at a dose of 50 mg/kg/day for five days. The mean blood lead level decreased 47.4% and the mean urinary lead excretion was 21 mg in the control patients.

Effect on Essential Minerals:   In the above studies succimer had no significant effect on the urinary elimination of iron, calcium or magnesium. Zinc excretion doubled during treatment. The effect of succimer on the excretion of essential minerals was small compared to that of CaNa ₂ EDTA, which can induce more than a ten-fold increase in urinary excretion of zinc and doubling of copper and iron excretion.

Efficacy:   A dose ranging study was performed in 15 pediatric patients aged 2 to 7 years with blood lead levels of 30-49 µg/dL and positive CaNa ₂ EDTA lead mobilization tests. Each group of five patients received 350, 233 or 116 mg/m ² succimer every 8 hours for 5 days. These doses corresponded to 10, 6.7 and 3.3 mg/kg. Six control patients received 1000 mg/m ² /day CaNa ₂ EDTA intravenously for 5 days. Following therapy, the mean blood lead levels decreased 78, 63 and 42% respectively in the three groups treated with succimer. The response of the 350 mg/m ² every 8 hours (10 mg/kg q 8 hr) group was significantly better than that of the other succimer treated groups as well as that of the control group, whose mean blood lead level fell 48%. No adverse reactions or changes in essential mineral excretion were reported in the succimer treated groups. In the CaNa ₂ EDTA treated group, the cumulative amount of urinary lead excreted was slightly but significantly greater than in the succimer group. After CaNa ₂ EDTA, the urinary excretion of copper, zinc, iron and calcium were significantly increased.

As with other chelators, both adults and pediatric patients experienced a rebound in blood lead levels after discontinuation of CHEMET. In these studies, after treatment with a dose of 350 mg/m ² (10 mg/kg) every 8 hours for five days, the mean lead level rebounded and plateaued at 60-85% of pretreatment levels two weeks after therapy. The rebound plateau was somewhat higher with lower doses of succimer and with intravenous CaNa ₂ EDTA.

In an attempt to control rebound of blood lead levels, 19 pediatric patients, ages 1-7 years, with blood lead levels of 42-67 µg/dL, were treated with 350 mg/m ² succimer every 8 hours for five days and then divided into three groups. One group was followed for two weeks with no further therapy, the second group was treated for two weeks with 350 mg/m ² daily, and the third with 350 mg/m ² every 12 hours. After the initial 5 days of therapy, the mean blood lead level in all subjects declined 61%. While the untreated group and the group treated with 350 mg/m ² daily experienced rebound during the ensuing two weeks, the group who received the 350 mg/ m ² every 12 hours experienced no such rebound during the treatment period and less rebound following cessation of therapy.

In another study, ten pediatric patients, ages 21 to 72 months, with blood lead levels of 30-57 µg/dL were treated with succimer 350 mg/m ² every eight hours for five days followed by an additional 19-22 days of therapy at a dose of 350 mg/m ² every 12 hours. The mean blood lead levels decreased and remained stable at under 15 µg/dL during the extended dosing period.

In addition to the controlled studies, approximately 250 patients with lead poisoning have been treated with succimer either orally or parenterally in open U.S. and foreign studies with similar results reported. Succimer has been used for the treatment of lead poisoning in one patient with sickle cell anemia and in five patients with glucose-6-phosphodehydrogenase (G6PD) deficiency without adverse reactions.

Lead Encephalopathy:   Three adults with lead encephalopathy have been reported in the literature to have improved with succimer therapy. However, data are not available regarding the use of succimer for the treatment of this rare and sometimes fatal complication of lead poisoning in pediatric patients.

Other Heavy Metal Poisoning:   No controlled clinical studies have been conducted with succimer in poisoning with other heavy metals. A limited number of patients have received succimer for mercury or arsenic poisoning. These patients showed increased urinary excretion of the heavy metal and varying degrees of symptomatic improvement.