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Berotralstat API Manufacturers & Suppliers

General Description:

Berotralstat, identified by CAS number 1809010-50-1, is a notable compound with significant therapeutic applications. Berotralstat is a selective inhibitor of plasma kallikrein used in the prophylaxis of attacks of hereditary angioedema (HAE). It works by blocking the enzymatic activity of plasma kallikrein in releasing bradykinin, the major biologic peptide that promotes swelling and pain associated with attacks of HAE. Berotralstat is strictly used to prevent, but not treat, these attacks. Developed by BioCryst Pharmaceuticals, berotralstat is marketed under the name Orladeyo as oral capsules. Berotralstat was first approved by the FDA on December 3, 2020, as the first once-daily oral therapy to prevent angioedema attacks of HAE in adults and pediatric patients 12 years and older. Berotralstat was approved by the European Commission on April 30, 2021 and by Health Canada on June 06, 2022.

Indications:

This drug is primarily indicated for: Berotralstat is indicated for prophylaxis of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older. It is not used for the treatment of acute HAE attacks. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Berotralstat undergoes metabolic processing primarily in: Berotralstat is metabolized by CYP2D6 and CYP3A4. The metabolic pathway and the metabolites of berotralstat have not yet been characterized. Following a single oral dose administration of 300 mg radiolabeled berotralstat, about 34% of the total plasma radioactivity accounted for the unchanged drug while about eight detectable metabolites accounted for 1.8 to 7.8% of the total radioactivity. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Berotralstat are crucial for its therapeutic efficacy: The steady-state of berotralstat is reached within 6 to 12 days following initial administration. After once-daily administration, the Cmax and AUC of berotralstat at steady-state is approximately five times that of the drug after a single dose. Following oral administration of berotralstat once-daily, the steady-state Cmax was 158 ng/mL (range: 110 to 234 ng/mL) at the dose of 150 mg and 97.8 ng/mL (range: 63 to 235 ng/mL) at the dose of 110 mg. The area under the curve over the dosing interval (AUCtau) was 2770 ng*hr/mL (range: 1880 to 3790 ng*hr/mL) and 1600 ng*hr/mL (range: 950 to 4170 ng*hr/mL) at the dose of 110 mg. The median Tmax is 2 hours in a fasted state and a high-fat meal delays the Tmax to 5 hours. The Tmax can range from 1 to 8 hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Berotralstat is an important consideration for its dosing schedule: Following a single oral dose administration of 300 mg radiolabeled berotralstat, the median elimination half-life of berotralstat was approximately 93 hours, ranging from 39 to 152 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Berotralstat exhibits a strong affinity for binding with plasma proteins: Plasma protein binding is approximately 99%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Berotralstat from the body primarily occurs through: Following a single oral dose administration of 300 mg radiolabeled berotralstat, approximately 9% of the drug was excreted in the urine, where 1.8 to 4.7% of the total radiolabeled compound accounted for the unchanged parent drug. About 79% of the drug was excreted in feces. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Berotralstat is distributed throughout the body with a volume of distribution of: The blood to plasma ratio was approximately 0.92 following a single 300 mg dose administration of radiolabeled berotralstat. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Berotralstat is a critical factor in determining its safe and effective dosage: There is no information on the clearance rate. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Berotralstat exerts its therapeutic effects through: Berotralstat prevents angioedema attacks by inhibiting plasma kallikrein, thereby regulating excess bradykinin generation in patients with hereditary angioedema (HAE). It had a fast onset of action, long duration of action, and acceptable tolerance in clinical trials. Berotralstat inhibits plasma kallikrein in a concentration-dependent. In clinical trials, berotralstat reduced HAE attack rates at 24 weeks, and its effects sustained through 48 weeks. In clinical trials, doses of berotralstat higher than 150 mg once daily led to QT Prolongation in a concentration-dependent manner. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Berotralstat functions by: Hereditary angioedema (HAE) is a rare genetic disorder associated with severe swelling of the skin and upper airway. It is caused by mutations in the regulatory or coding regions of the gene that encodes C1 inhibitor (SERPING1), which result in either a deficiency (type I) or dysfunction (type II) of C1 inhibitor (C1 esterase inhibitor, C1-INH). C1 inhibitor is a serine protease inhibitor that normally regulates bradykinin production by covalently binding to and inactivating plasma kallikrein. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK). During HAE attacks, the levels of plasma kallikrein fall, leading to the cleavage of high-molecular-weight-kininogen and the release of bradykinin, a potent vasodilator that increases vascular permeability. Bradykinin plays a major role in promoting edema and pain associated with HAE. Patients with HAE cannot properly regulate plasma kallikrein activity due to the deficiency or dysfunction of a serum inhibitor of C1 inhibitor, leading to uncontrolled increases in plasma kallikrein activity and recurrent angioedema attacks. Berotralstat is a potent inhibitor of plasma kallikrein that works by binding to plasma kallikrein and blocking its proteolytic activity, thereby controlling excess bradykinin generation. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Berotralstat is categorized under the following therapeutic classes: BCRP/ABCG2 Substrates, Blood and Blood Forming Organs, Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (moderate), Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (moderate), Cytochrome P-450 Enzyme Inhibitors, Drugs Used in Hereditary Angioedema, Enzyme Inhibitors, Kallikrein Inhibitors, Kallikreins, antagonists & inhibitors, Moderate Risk QTc-Prolonging Agents, P-glycoprotein inhibitors, P-glycoprotein substrates, Plasma Kallikrein Inhibitor, Protease Inhibitors, QTc Prolonging Agents, Serine Protease Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.