Avacopan API Manufacturers

General Description:

Avacopan, identified by CAS number 1346623-17-3, is a notable compound with significant therapeutic applications. Anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis (AAV) is a rare (estimated incidence of 3 cases per 100,000 per year) form of "pauci-immune" systemic small-vessel vasculitis typified by the presence of ANCAs in the serum. The full spectrum of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. AAV may be associated with necrotizing and crescentic glomerulonephritis (NCGN). Despite complex pathophysiology, studies over the past ~2 decades have identified a key role for the alternative complement pathway and, in particular, the interaction between the anaphylatoxin fragment C5a and its cognate C5aR receptor in AAV. Avacopan (formerly CCX168) is an allosteric C5aR antagonist indicated for use in AAV. Avacopan was granted FDA approval on October 8, 2021, and is currently marketed under the name TAVNEOS by ChemoCentryx, Inc. On January 19, 2022, the European Commission approved avacopan for the treatment of adult patients with severe, active granulomatosis polyangiitis (GPA) or microscopic polyangiitis (MPA) - the two main forms of ANCA-associated vasculitis - in combination with or . Avacopan was approved by Health Canada on April 20, 2022.

Indications:

This drug is primarily indicated for: Avacopan is indicated for the adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis; GPA/MPA) in combination with standard therapy including glucocorticoids. Avacopan does not eliminate the need for glucocorticoids. In Europe, avacopan is approved for the treatment of adults with severe, active granulomatosis polyangiitis (GPA) or microscopic polyangiitis (MPA) in combination with rituximab or cyclophosphamide. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Avacopan undergoes metabolic processing primarily in: Avacopan is metabolized primarily by CYP3A4. The major circulating M1 metabolite, a mono-hydroxylated form of avacopan, represents ~12% of drug plasma levels and acts as a C5aR antagonist with similar efficacy to avacopan itself. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Avacopan are crucial for its therapeutic efficacy: In AAV patients receiving 30 mg avacopan twice daily, avacopan had a C_max of 349 ± 169 ng/mL and an AUC_0-12hr of 3466 ± 1921 ng\*h/mL. On this dosing scheme, steady-state plasma concentrations are reached by 13 weeks with a roughly 4-fold accumulation. Co-administration of 30 mg with a high-fat meal increased the C_max by ~8%, the AUC by ~72%, and delayed the T_max by four hours (from two hours). The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Avacopan is an important consideration for its dosing schedule: A single 30 mg dose of avacopan given with food to healthy subjects resulted in mean elimination half-lives of 97.6 and 55.6 hours for avacopan and its M1 metabolite, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Avacopan exhibits a strong affinity for binding with plasma proteins: Avacopan and its M1 metabolite are more than 99.9% bound to plasma proteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Avacopan from the body primarily occurs through: Avacopan is mainly eliminated in feces, with smaller amounts present in the urine. Following oral administration of the radiolabeled drug, roughly 77% (7% as unchanged avacopan) was recovered in feces while 10% (<0.1% unchanged) was recovered in urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Avacopan is distributed throughout the body with a volume of distribution of: Avacopan has an apparent volume of distribution of 345 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Avacopan is a critical factor in determining its safe and effective dosage: Avacopan has an estimated total apparent body clearance (CL/F) of 16.3 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Avacopan exerts its therapeutic effects through: Avacopan is a complement 5a receptor (C5aR) antagonist that blocks C5a-induced upregulation of C11b (integrin alpha M) on neutrophils and inhibits C5a-mediated neutrophil activation and migration. Avacopan has been associated with hypersensitivity reactions, including angioedema, and hepatotoxicity, as evidenced by elevated liver transaminases. Likely due to its effect on the complement pathway, avacopan has also been associated with hepatitis B virus reactivation and serious infections, which should be monitored for as appropriate. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Avacopan functions by: Anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis (AAV) is considered a "pauci-immune" form of systemic small-vessel vasculitis accompanied by the presence of ANCAs in the serum. The full spectrum of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. AAV may be associated with necrotizing and crescentic glomerulonephritis (NCGN). Of the various known ANCAs, the major antigens are myeloperoxidase (MPO) and proteinase 3 (PR3/myeloblastin). The pathophysiology giving rise to AAV is complex, though a working model has been proposed. An initial trigger, such as infection, causes differentiation of naive T cells into T_H17 helper T cells that induce the release from macrophages of pro-inflammatory cytokines (e.g, TNF-α and IL-1β), which prime neutrophils. Concurrently, the anaphylatoxin C5a is produced through activation of the alternative complement pathway, which also primes neutrophils through binding to the C5a receptor (C5aR; CD88). Primed neutrophils undergo physiological changes, including upregulating the display of ANCA antigens on their surface. Circulating ANCAs bind to displayed ANCA antigens on the surface of neutrophils; simultaneously, the Fc region of these ANCAs is recognized by Fcγ receptors on other neutrophils, resulting in excessive neutrophil activation. Activated neutrophils form NETs (neutrophil extracellular traps), which induce tissue damage and vasculitis. MPO/PR3 in NETs induces further ANCA production through dendritic cell- and CD4⁺ T cell-mediated activation of B cells, further exacerbating the condition. A role for complement was not initially considered in AAV due to a lack of excessive complement or immunoglobulin deposition in AAV lesions. However, extensive molecular studies confirmed a significant role for the alternative complement pathway, acting through C3 and C5, in the pathogenesis of AAV. The C5a fragment, generated by C5 cleavage, can bind to both the C5aR and C5a-like receptor (C5L2) on the surface of neutrophils; C5aR binding is associated with AAV while C5L2 binding has a protective effect. As the alternative complement pathway is self-sustaining in the absence of down-regulation by specific proteins, it is likely a significant driver of AAV. Furthermore, neutrophils activated by C5a release reactive oxygen species, properdin, and other molecules that stimulate the complement pathway leading to the production of more C5a in a vicious cycle. Avacopan (CCX168) is a specific C5aR receptor allosteric antagonist that inhibits C5a-mediated neutrophil activation both _in vitro_ and _in vivo_. By inhibiting the C5a/C5aR axis, avacopan should have minimal effects on the formation of the membrane attack complex (which includes C5b) and therefore little effect on the innate immune response in treated patients. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Avacopan belongs to the class of organic compounds known as 1-benzoylpiperidines. These are compounds containing a piperidine ring substituted at the 1-position with a benzoyl group, classified under the direct parent group 1-benzoylpiperidines. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Benzene and substituted derivatives class, specifically within the Benzoyl derivatives subclass.

Categories:

Avacopan is categorized under the following therapeutic classes: Amines, Complement 5a Receptor Antagonist, Cytochrome P-450 CYP1A2 Inducers, Cytochrome P-450 CYP1A2 Inducers (strength unknown), Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (strength unknown), Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C9 Inhibitors (strength unknown), Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (strength unknown), Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (strength unknown), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, P-glycoprotein substrates, Piperidines. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.