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General Description:

Lanadelumab, identified by CAS number 1426055-14-2, is a notable compound with significant therapeutic applications. Lanadelumab, also known as DX-2930, is a human IgG1 monoclonal antibody designed for subcutaneous self-injection. It is a fully human immunoglobulin, k-light-chain made in recombinant Chinese Hamster Ovary cells. The FDA and EU granted the designation of priority review, breakthrough therapy and orphan drug for rare diseases based on the results of the reported clinical trials. Lanadelumab was developed by Shire and FDA approved on August 28, 2018.

Indications:

This drug is primarily indicated for: Lanadelumab is indicated for the prophylaxis treatment to prevent attacks in patients 12 years and older with hereditary angioedema. The hereditary angioedema (HEA) is an autosomal dominant disorder resulted from the presence of C1 deficiency. Some reports have indicated a high prevalence of cases that result from spontaneous mutations which can be inherited. This condition is manifested by attacks of subcutaneous or submucosal edema in the face, larynx, GI tract, limbs or genitalia. From all the types of attacks, the most serious is the laryngeal as it can compromise the airway. The rest of the attacks are accompanied by pain and considerable dysfunction. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lanadelumab undergoes metabolic processing primarily in: Because lanadelumab is a protein, it is expected to be degraded into small peptides and amino acids by proteolytic enzymes. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lanadelumab are crucial for its therapeutic efficacy: The drug levels of lanadelumab are dose-dependent and thus, the maximum plasma concentration increased correspondingly with an increased dosage. The Cmax and AUC ranged from 3800 to 45000 ng/ml and from 64000 to 762000 ng.day/ml respectively for concentrations from 30 to 400 mg. As well, sustained quantifiable drug concentration was observed through day 120. The bioavailability of lanadelumab is of approximately 66% with a time to reach peak drug concentration of approximately 7 days. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lanadelumab is an important consideration for its dosing schedule: Lanadelumab has a prolonged half-life which is typical of a human monoclonal antibody and it ranged from 13.8 to 15 days. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Lanadelumab exhibits a strong affinity for binding with plasma proteins: General information on plasma protein binding is not available but it is considered that, as the site of action is with plasma proteins, the percentage of protein binding should be significant. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Lanadelumab from the body primarily occurs through: The main excretion is thought to be done in the urine but this has not been confirmed and further studies are required. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lanadelumab is distributed throughout the body with a volume of distribution of: The reported volume of distribution of lanadelumab is in the range of 12 to 16 L which variates according to the dose administered. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Lanadelumab is a critical factor in determining its safe and effective dosage: The apparent total plasma clearance after extravascular administration ranges between 18 and 25 ml/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Lanadelumab exerts its therapeutic effects through: In phase 1 studies, the level of kininogen, the substrate of kallikrein, was studied as a marker of kallikrein activity. In patients with C1 deficiency, the level of cleaved kininogen is 4-fold higher when compared with C1-normal individuals. When lanadelumab was administered, the levels of cleaved kininogen were significantly reduced with a dose of 300 and 400 mg of lanadelumab with a maximum reduction at day 22 corresponding with time for maximum concentration. This maximum reduction corresponded with the normal levels of cleaved kininogen. Similarly, the decreases of cleaved kininogen corresponded as well with reductions in the levels of the activated factor XII. Clinically, the attacks of angioedema completely vanished in the patients receiving a dose of 300 mg of lanadelumab. In other doses such as 400 mg and combo 300/400 mg the attack reduction reached 90%. In phase 3 clinical trials (HELP study, lanadelumab showed an attack rate reduction of over 70% for all three different dose regimes. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lanadelumab functions by: Lanadelumab is a plasma kallikrein inhibitor. This enzyme works by cleaving high molecular weight kininogen to generate the pro-inflammatory peptide bradykinin which is a potent vasodilator. The activity of plasma kallikrein is regulated by the activity of C1-inhibitor and thus, the patients that are deficient in C1 are known to be correlated to excessive production of bradykinin which will further lead to fatal angioedema. Hence, lanadelumab occludes the proteolytic active site of plasma kallikrein, preventing the cleavage of kininogen to bradykinin. It is a selective inhibitor as it has been reported that lanadelumab does not bind to prekallikrein or to inhibit any other serine proteases. The activity of lanadelumab works as an additional checkpoint for the patients suffering from C1 deficiency. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Lanadelumab belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Lanadelumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Blood and Blood Forming Organs, Blood Proteins, Drugs Used in Hereditary Angioedema, Globulins, Immunoglobulins, Immunoproteins, Kallikrein Inhibitors, Plasma Kallikrein Inhibitor, Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Lanadelumab include:

• Water Solubility: 50 mg/ml
• Melting Point: 80-90 ºC (based on IgG properties)
• Boiling Point: Fab and Fc domains denaturates at 60 and 70 ºC respectively
• Isoelectric Point: 6.1-8.5
• Molecular Weight: 146000.0
• Molecular Formula: C6468H10016N1728O2012S47