| Primary information |
|---|
| ThPP ID | Th1117 |
| Therapeutic Peptide/Protein Name | Ipilimumab |
| Sequence | Heavy chain:QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVR view full sequnce in fasta |
| Functional Classification | IIIc |
| Molecular Weight | 148000 |
| Chemical Formula | C6572H10126N1734O2080S40 |
| Isoelectric Point | N.A. |
| Hydrophobicity | N.A. |
| Melting Point (℃) | N.A. |
| Half Life | Terminal Elimination Half-life: 14.7 -15.4 days |
| Description | Recombinant, human monoclonal IgG1 kappa immunoglobin. It is an antineoplastic agent developed by Bristol-Myers Squibb and Medarex for the treatment of unresectable or metastatic melanoma in adults. Ipilimumab received FDA approval on March 25, 2011. |
| Indication/Disease | Ipilimumab is indicated for the treatment of unresectable or metastatic melanoma in adults. |
| Pharmacodynamics | 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. |
| Mechanism of Action | Ipilimumab is a fully human IgG1K 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. |
| Toxicity | 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 |
| Metabolism | 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. |
| Absorption | In one pharmacokinetic study of patients with unresectable or metastatic melanoma peak concentrations, trough concentrations, and area under the curve (AUC) were found to be dose proportional in the dosage range examined (0.3, 3, or 10mg/kg every 3 weeks for four doses). |
| Volume of Distribution | Volume of distribution at steady state = 7.21 L |
| Clearance | Clearance was measured to be 15.3mL/hr-16.8 mL/hr.In one pharmacokinetic study examining ipilimumab administered every 3 weeks, clearance was found to be time invariant. Minimal systemic accumulation was observed (accumulation index of 1.5 fold or less).Steady state concentrations was reached by the third dose.Clearance will increase with increasing body weight; however, no dose adjustment is needed if administration occurs on a mg/kg basis. The following had no clinically meaningful influence o |
| Categories | Antineoplastic Agents and Monoclonal antibodies |
| Patents Number | CA2381770 |
| Date of Issue | 08/08/11 |
| Date of Expiry | 09/08/24 |
| Drug Interaction | N.A. |
| Target | Cytotoxic T-lymphocyte protein 4 |
| Information of corresponding available drug in the market |
|---|
| Brand Name | YERVOY |
| Company | Bristol-Myers Squibb |
| Brand Discription | YERVOY (ipilimumab) is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. |
| Prescribed for | YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for the treatment of unresectable or metastatic melanoma |
| Chemical Name | N.A. |
| Formulation | It is supplied in single-use vials of 50 mg/10 mL and 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7. |
| Physcial Appearnce | Sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution |
| Route of Administration | N.A. |
| Recommended Dosage | The recommended dose of YERVOY is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses. |
| Contraindication | Immune-mediated adverse reactions: Permanently discontinue for severe reactions. Less than 7.5 mg prednisone or equivalent per day is administered or systemic high-dose corticosteroids are adminstered for severe, persistent, or recurring immune-mediated reactions. |
| Side Effects | Most common adverse reactions (≥5%) are fatigue, diarrhea, pruritus, rash, and colitis. |
| Useful Link | http://www.rxlist.com/yervoy-drug.htm http://packageinserts.bms.com/pi/pi_yervoy.pdf http://www.yervoy.com/patient.aspx |
| PubMed ID | 25658618, 25658617, 25649350, 25647225, 25641691 |
| 3-D Structure | Th1117 Heavy chain or (Download), Th1117 Light chain (View) or (Download) |