| Primary information |
|---|
| ThPP ID | Th1106 |
| Therapeutic Peptide/Protein Name | Insulin detemir |
| Sequence | A chainGIVEQCCTSICSLYQLENYCN B chain FVNQHLCGSHLVE view full sequnce in fasta |
| Functional Classification | Ia |
| Molecular Weight | 5916.9 |
| Chemical Formula | C267H402N64O76S6 |
| Isoelectric Point | N.A. |
| Hydrophobicity | N.A. |
| Melting Point (℃) | N.A. |
| Half Life | Adults (18-65 years) = 425 ± 78 minutes |
| Description | Recombinant (from yeast cells), long-acting human insulin analogue. It has a myristic acid (14-C fatty acid), bound to lysine at position B29, which increases self-association and albumin binding. Coupled with its slow systemic absorption from the injection site, prolongs its distribution into tissues enabling it to act for a longer time than native insulin. |
| Indication/Disease | For the treatment of type 1 or 2 diabetes mellitus. May be used in combination with oral anti-diabetic agents in type 2 diabetic patients who are not in adequate metabolic control with oral anti-diabetic agents alone. |
| Pharmacodynamics | Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin. |
| Mechanism of Action | Insulin detemir binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism.
Insulin detemir's long duration of action appears to be a result of slow systemic absorption from the injection site and delayed distribution to target tissues. The myristic acid side chain on insulin detemir increases self-association and gives it a high binding affinity to serum albumin. These features slows its distribution into target tissues and prolongs its duration of action. |
| Toxicity | Hypoglycemia may occur with inappropriately high doses. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. Injection site reactions may also occur. Symptoms include: redness, inflammation, bruising, swelling and itching at the injection site. |
| Metabolism | As with natural insulin, all metabolites formed are inactive. |
| Absorption | Maximum serum concentrations are reached 6 to 8 hours following subcutaneous injection. When single dose of 0.5 units/kg of insulin detemir was given to adult type 1 diabetes patients, the maximum serum concentration (Cmax) was 4,641 ± 2,299 pmol/L. Absorption is also dependent on the site of injection. When injected into the thigh, the AUC was lower than when injected into the deltoid and abdominal regions. Bioavailability is approximately 60%. |
| Volume of Distribution | 0.1 L/kg |
| Clearance | Apparent clearance (CL/F), type 1 diabetes adult patients = 3.41 ± 1.00 L/min·kg |
| Categories | Antidiabetic Agents |
| Patents Number | US5750497 |
| Date of Issue | 17/05/03 |
| Date of Expiry | 17/05/23 |
| Drug Interaction | N.A. |
| Target | Insulin receptor |
| Information of corresponding available drug in the market |
|---|
| Brand Name | LEVEMIR |
| Company | Novo Nordisk |
| Brand Discription | LEVEMIR (insulin detemir [rDNA origin] injection) is a sterile solution of insulin detemir for use as a subcutaneous injection. Insulin detemir is a long-acting (up to 24-hour duration of action) recombinant human insulin analog. LEVEMIR is produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a molecular formula of C267H402O76N64S6 and a molecular weight of 5916.9 |
| Prescribed for | LEVEMIR is indicated to improve glycemic control in adults and children with diabetes mellitus. |
| Chemical Name | N.A. |
| Formulation | Each milliliter of LEVEMIR contains 100 units (14.2 mg/mL) insulin detemir, 65.4 meg inc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has a pH of approximately 7.4 |
| Physcial Appearnce | Clear, colorless, aqueous, neutral Sterile solution |
| Route of Administration | Subcutaneous |
| Recommended Dosage | Patients who require twice-daily dosing can administer the evening dose with the evening meal, at bedtime, or 12 hours after the morning dose. The dose of LEVEMIR must be individualized based on clinical response. Blood glucose monitoring is essential in all patients receiving insulin therapy. |
| Contraindication | LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition. LEVEMIR is contraindicated in patients with hypersensitivity to LEVEMIR or any of its excipients. Reactions have included anaphylaxis. |
| Side Effects | Hypoglycemia, upper respiratory tract infection, Headache, Pharyngitis, Influenza-like illness, Abdominal Pain |
| Useful Link | http://www.rxlist.com/levemir-drug.htm http://www.drugs.com/levemir.html http://www.webmd.com/drugs/2/drug-95095/levemir-subq/details http://www.levemir.com/considering-levemir/levemir-flextouch/ |
| PubMed ID | 23512415, 18454569, 18034591, 17881328, 17901036, 14578244, 23551900, 17443605, 14578244 |
| 3-D Structure | Th1106 A chain or (Download),Th1106 B chain (View) or (Download) |