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Ipilimumab is a fully human IgG1κ antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on T-cells that is indicated for unresectable or metastatic melanoma. The absence or presence of CTLA-4 can augment or suppress the immune system’s T-cell response in fighting disease. Ipilimumab is designed to block the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells. The proposed mechanism of action is indirect, and may be through T-cell – mediated anti-tumor immune responses.
The pharmacodynamics of Ipilimumab are not completely understood. In melanoma patients receiving Ipilimumab, the mean peripheral blood absolute lymphocyte counts (ALC) increased throughout the induction dosing period. This increase occurred in a dose-dependent fashion in Phase 2 studies. Ipilimumab given with or without gp100 at 3 mg/kg increased ALC throughout the induction dosing period, but no meaningful change in ALC occurred in the control group who received an investigational peptide vaccine alone. Furthermore, ipilimumab binds to CTLA-4 with high affinity (Kd = 5.24 ± 3.62 nM). As a result, ligands CD80 and CD86 are blocked from binding to CTLA-4 with a minimum EC50 value of 0.2 μg/mL.
The metabolism of ipilimumab does not involve the cytochrome P450 enzyme system. Because ipilimumab is a protein it is expected to be degraded into small peptides and amino acids by proteolytic enzymes.
Therapy with Ipilimumab can result in severe and fatal immune reactions due to T-cell proliferation and activation. These reactions may occur in multiple organ systems, but common reactions include enterecolitis, dermatitis (including toxic necrolysis), neuropathy, and endocrinopathy. Patients should be assessed for signs and symptoms of enterocolitis (diarrhea, abdominal pain, mucus/blood in stool), bowel perforation (petitoneal signs and ileus), hepatitis, dermatitis (rash and pruritus), motor or sensory neuropathy (unilateral/bilateral weakness, sensory alterations, or paresthesia) , hypophysitis/adrenal insufficiency including adrenal crisis/hyper- or hypothyroidism (fatigue, mental status change, abdominal pain, unusual bowel habits, hypotension) and should have liver function tests and thyroid function tests performed at baseline and prior to each dose. Typically immune mediated adverse reactions manifest during therapy, however, a minority of reactions occurred after discontinuation of ipilimumab. In one study of neuropathies, one case of fatal Guillain-Barré syndrome occurred, and once case of severe peripheral neuropathy (Grade 3) was reported. During clinical development of ipilimumab additional cases of Guillain-Barré and myasthenia gravis have been reported. In severe neuropathy, permanently discontinue ipilimumab, and initiate 1-2mg/kd/day of prednisone or equivalent. In one study, severe or potentially fatal dermatitis (eg, Steven-Johnsons syndrome (SJS) or toxic epidermal necrolysis (TEN)) occured in 2.5% (n=13). The median time of onset of moderate to potentially fatal dermatitis was 3.1 weeks (up to 17.3 weeks). Treatment of 54% of severe dermatitis cases (n=7) involved high dose topical corticosteriods. 6 patients had complete resolution in up to 15.6 weeks. Permanently discontinue ipilimumab in patients with SJS or TEN, and withhold the dose in patients with moderate to severe signs and symptoms. Mild- moderate dermatitis (localized rash and pruritus) may be treated symptomatically. If no improvement is seen in 1 week administer topical or systemic corticosteroids. In one study of endocrinopathies, severe to life threatening endocrinopathies occurred in 1.8% (n=9) of patients, with all 9 patients having hyopituitarism and some having adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized. Moderate endocrinopathies occurred in 2.3% of patients (n=12) and required hormone replacement or medical intervention. The median time of onset was 11 weeks. In symptomatic patients, withhold ipilimumab, and initiate 1-2mg/kd/day of prednisone or equivalent and appropriate hormone replacement therapy. In one study of enterocolitis in 511 patients, diarrhea of ≥7 stools above baseline, fever, ileus and peritoneal signs (Grade 3-5, severe, potentially fatal enterocolitis) occured in 7% (n=34) of patients treated with ipilimumab. Diarrhea of up to 6 stools above baseline, abdominal pain, mucus or blood in stool (Grade 2, moderate enterocolitis) occurred in 5% of patients (n=28). Intestinal perforation occurred in 1% (n=5). Death as a result of complications occurred in 0.8% (n=4). Hospitalization for severe enterocolitis occurred in 5% (n=26). Grade 3-5 enterocolitis had a median time of onset of 7.4 weeks (with a range of 1.6-13.4 weeks). Grade 2 entercolitis had a median time of onset of 6.3 weeks (with a range of 0.3- 18.9 weeks). Treatment of 85% (n=29) of patients with Grade 3-5 enterocolitis (n=34) included high dose corticosteroids (≥40mg/day prednisone equivalent). Median dose used was 80mg/day of prednisone/equivalent for a median duration of 2.3 weeks (up to 13.9 weeks). Of the 34 patients, 74% experienced complete resolution, 3% progressed to Grade 2 severity, and 24% exhibited no improvement. In treatment of 28 patients with a Grade 2 enterocolitis: 25% received high dose corticosteroids for a median of 10 days; 29% of patients received a non-high dose of corticosteroids (<40mg/day of prednisone/equivalent) for a median duration of 5.1 weeks; 46% did not receive systemic corticosteroids. Of the 28 patients, 79% of patients experienced complete resolution, 11% improved in severity, 11% exhibited no improvement. In patients with severe enterocolitis, permanently discontinue ipilimumab, and initiate 1-2 mg/kd/day of prednisone or an equivalent. Once patient improvement to Grade 1 or less is seen, taper the corticosteroid over at least one month. In patients with moderate enterocolitis, hold dose of ipilimumab, and initiate 0.5 mg/kd/day of prednisone or an equivalent. In another study examining immune mediated hepatitis, AST or ALT elevation of ≥3 times the upper limit of normal (ULN) (severe and potentially fatal hepatotoxicity) was seen in 2% (n=8) of patients on ipilimumab. Fatal hepatic failure occurred in 0.2%. Hospitalization occurred in 0.4%. Additionally, moderate hepatotoxicity (2.5xULN >ALT or AST> 5xULN, or 1.5xULN>bilirubin>3xULN ) occurred in 2.5% (n=13). In Grade 3-5 hepatotoxicity, permanently discontinue ipilimumab, and initiate 1-2mg/kd/day of prednisone or equivalent. Once LFT show sustained improvement taper corticosteroid over 1 month. In Grade 2 hepatotoxicity, withhold ipilimumab. In pregnancy, use only if potential benefit justifies potential risk to fetus (Category C). In studies done in monkeys, severe toxicities were observed including abortion, stillbirth, low birth weight and infant mortality. Additionally, ipilimumab has the potential to cross the placental barrier, and it is unknown if secretion into breast milk occurs. No studies have been performed to study carcinogenesis, mutagenesis, and impairment of fertility.
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