| Primary information |
|---|
| ThPP ID | Th1123 |
| Therapeutic Peptide/Protein Name | Denosumab |
| Sequence | Heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVR view full sequnce in fasta |
| Functional Classification | IIIc |
| Molecular Weight | 144700 |
| Chemical Formula | C6404H9912N1724O2004S50 |
| Isoelectric Point | N.A. |
| Hydrophobicity | N.A. |
| Melting Point (℃) | N.A. |
| Half Life | 25.4 days |
| Description | Novel, fully human IgG2 monoclonal antibody, specific to receptor activator of nuclear factor kappa-B ligand (RANKL). It suppresses bone resorption markers in patients suffering from metastatic tumors and is being investigated in multiple clinical trials for the prevention and treatment of bone metastases. Each light chain consists of 215 amino acids and the heavy chain consists of 448 amino acids. FDA approved on June 1, 2010. |
| Indication/Disease | Prolia is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture. It reduces the incidence of vertebral, nonvertebral, and hip fractures. Prolia is also indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. It can also be used in men with osteoporosis at high risk for fracture or in men receiving androgen deprivation therapy for nonmetastatic prostate cancer to increase bone mass. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. |
| Pharmacodynamics | In clinical studies, treatment with 60 mg of Prolia resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days. Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e. osteocalcin and procollagen type 1 N-terminal peptide [PlNP]) were observed starting 1 month after the first dose of Prolia. |
| Mechanism of Action | Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. |
| Toxicity | In patients with postmenopausal osteoporosis, the most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials. In male patients with osteoporosis, the most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis. In patients experiencing bone loss due to hormone ablation for cancer, the most common adverse reactions (≥ 10% and more common than placebo) were: arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials |
| Metabolism | N.A. |
| Absorption | When 60 mg of denosumab was subcutaneously administered to healthy subjects after fasting for 12 hours, the pharmacokinetic parameters are as follows: Cmax = 6.75 mcg/mL; Tmax= 10 days (range of 3 to 21 days); AUC (0-16 weeks) = 316 mcg day/mL. Denosumab does not accumulate following multiple doses once every 6 months. The pharmacokinetics of denosumab were not affected by the formation of antibodies. |
| Volume of Distribution | N.A. |
| Clearance | N.A. |
| Categories | Bone Density Conservation Agents and Monoclonal antibodies |
| Patents Number | CA2257247 |
| Date of Issue | 12/09/16 |
| Date of Expiry | 16/04/22 |
| Drug Interaction | N.A. |
| Target | Tumor necrosis factor ligand superfamily member 11 |
| Information of corresponding available drug in the market |
|---|
| Brand Name | Xgeva |
| Company | Amgen. |
| Brand Discription | Xgeva (denosumab) is a human IgG2 monoclonal antibody that binds to human RANKL. Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells. |
| Prescribed for | Bone Metastasis From Solid Tumors, Giant Cell Tumor Of Bone, Hypercalcemia Of Malignancy |
| Chemical Name | N.A. |
| Formulation | Each single-use vial of Xgeva contains 120 mg denosumab, acetate (18 mM), sorbitol (4.6%), Water for Injection (USP), and sodium hydroxide to a pH of 5.2 |
| Physcial Appearnce | Sterile, preservative-free, clear, colorless to pale yellow solution |
| Route of Administration | N.A. |
| Recommended Dosage | Bone Metastasis From Solid Tumors: The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.; Giant Cell Tumor Of Bone: The recommended dose of Xgeva is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.; Hypercalcemia Of Malignancy: The recommended dose of Xgeva is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. |
| Contraindication | Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. |
| Side Effects | Hypocalcemia, Osteonecrosis of the Jaw. |
| Useful Link | http://www.rxlist.com/xgeva-drug.htm http://www.xgeva.com/ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm234346.htm |
| PubMed ID | 23159111, 16872263 |
| 3-D Structure | Th1123 Heavy chainor (Download)Th1123 Light chain (View) or (Download) |