DB08914 OCRIPLASMIN C1214H1890N338O348S14 27.25 kDa CATEGORY Hypoglycemic Agents and Antidiabetic Agents

DESCRIPTION Isophane insulin or NPH insulin (neutral protamine Hagedorn) is an intermediate-acting insulin to improve glycemic control. It is synthesized using a strain of Escherichia coli bacteria that has been genetically altered to produce human insulin. Human insulin isophane suspension consists of a crystalline suspension of human insulin with protamine and zinc. This combination results in an intermediate-acting insulin with a slower onset of action and longer duration of activity than regular human insulin. INDICATION Used to improve glycemic control in patients with type 1 or type 2 diabetes mellitus. PHARMACODYNAMICS When 0.3 Units/kg of NPH insulin was subcutaneously administered, the onset of action was approximately 0.8 hours. The duration of action was 13.2 hours. The peak activity of NPH insulin occurs 4-6 hours post-dose. Compared to insulin glargine, NPH insulin has a quicker onset of action and shorter duration of action.

MECHANISM OF ACTION The primary activity of insulin is the regulation of glucose metabolism. Insulin promotes glucose and amino acid uptake into muscle and adipose tissues, and other tissues except brain and liver. It also has an anabolic role in stimulating glycogen, fatty acid, and protein synthesis. Insulin inhibits gluconeogenesis in the liver. Insulin 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 is able to autophosphorylate and phosphorylate numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. These activated proteins, in turn, lead 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) which play a critical role in metabolism and catabolism TOXICITY Hypoglycemia is one of the most frequent adverse events experienced by insulin users

METABOLISM Insulin is predominantly cleared by metabolic degradation via a receptor-mediated process ABSORPTION Absorption does not differ if it is subcutaneously administered in the thigh or abdomen. when 0.5 IU/kg of NPH insulin was given to adult type 1 diabetes patients before breakfast, the pharmacokinetic parameters are as follows: AUC (0-24hours) = 111,941 ± 77,941 pmol · l-1 · min-1; Cmax = 149 ± 121 pmol/l; Tmax = 480 ± 237 minute. It is important to note that NPH insulin has a high degree of patient variability in its absorption profile. ROUTE OF ELIMINATION The route of elimination of certolizumab pegol has not been studied in human subjects. Studies in animals indicate that the major route of elimination of the PEG component is via urinary excretion. VOLUME OF DISTRIBUTION = 0.15 L/kg

SEQUENCE >Protein sequence for the truncated heavy chain APSFDCGKPQVEPKKCPGR>Protein sequence for the light chain VVGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAH QEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECF ITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDS GGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN TARGETS Insulin receptor

Jetrea (ThromboGenics Inc) Intravitreal injection Ocriplasmin is a recombinant truncated form of human plasmin with a molecular weight of 27.2 kDa produced by recombinant DNA technology in a Pichia pastoris expression system. JETREA is a sterile, clear and colorless solution with no preservatives in a single-use glass vial containing 0.5 mg ocriplasmin in 0.2 mL solution for intravitreal injection after dilution. Each vial contains 0.5 mg ocriplasmin (active) and 0.21 mg citric acid, 0.75 mg mannitol, sodium hydroxide (for pH adjustment) and water for injection. The pH of the solution is 3.1.

DOSAGE: 0.125 mg (0.1 mL of the diluted solution) administered by intravitreal injection to the affected eye once as a single dose. CLEARANCE: Ocriplasmin enters the endogenous protein catabolism pathway through which it is rapidly inactivated via its interactions with protease inhibitor α2-antiplasmin or α2-macroglobulin. HALF-LIFE: 24 hours post injection the levels in the vitreous were below 3% of the theoretical concentration reached immediately after injection. Because of the small dose administered (0.125 mg), detectable levels of ocriplasmin in systemic circulation are not expected after intravitreal injection. ADVERSE REACTION: Vitreous floaters, conjunctival hemorrhage, eye pain, photopsia, blurred vision, macular hole, reduced visual acuity, visual impairment, and retinal edema.

REFERENCES http://www.ncbi.nlm.nih.gov/pubmed/23917386 http://www.ncbi.nlm.nih.gov/pubmed/23794431