Find, compare & contact
Brincidofovir API Manufacturers & Suppliers

General Description:

Brincidofovir, identified by CAS number 444805-28-1, is a notable compound with significant therapeutic applications. Brincidofovir is an oral antiviral drug used in the treatment of human smallpox infections. It is a lipid conjugate pro-drug of the acyclic nucleotide analogue - this lipid conjugate improves drug delivery to the target cells and significantly reduces the nephrotoxicity typically associated with cidofovir therapy. Due to its formulation as a pro-drug brincidofovir also carries a greater bioavailability than cidofovir, allowing for oral administration rather than intravenous. Cidofovir itself has broad antiviral activity against several DNA viruses, resulting in brincidofovir being investigated for the prevention and treatment of cytomegalovirus (CMV), BK Virus (BKV), adenoviruses (AdV), and Epstein-Barr virus (EBV), amongst others. Brincidofovir, developed by Chimerix under the brand name Tembexa, was approved by the FDA for the treatment of smallpox infection in June 2021. As smallpox has been eradicated, the efficacy of Tembexa was assessed in animals infected with viruses closely related to variola. The approval was granted under the agency’s Animal Rule, which allows for a drug to be approved based on the results of well-controlled animal studies when human trials would be unethical or infeasible.

Indications:

This drug is primarily indicated for: Brincidofovir is indicated for the treatment of human smallpox disease in adult and pediatric patients. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Brincidofovir undergoes metabolic processing primarily in: Brincidofovir is a pro-drug of and as such must undergo some basic metabolic reactions to become pharmacologically active. Upon entering the target cell, the phosphodiester bond of brincidofovir is hydrolyzed to generate cidofovir, which is then phosphorylated to generate the active agent: cidofovir diphosphate. The specific enzyme(s) responsible for this reaction have not been elucidated, but _in vitro_ findings suggest sphingomyelin phosphodiesterase plays a major role in the initial hydrolysis of brincidofovir. There are two major inactive metabolites of brincidofovir, CMX103 and CMX064, which are generated via carboxylation of the terminal carbon followed by several cycles of CYP-mediated oxidative reactions and fatty acid oxidation. These reactions are mediated, at least in part, by CYP4F2. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Brincidofovir are crucial for its therapeutic efficacy: The oral bioavailability of brincidofovir is 13.4% in its tablet formulation and 16.8% in its suspension formulation. Following oral administration, the C_max and AUC_tau of brincidofovir were 480 ng/mL and 3400 ng·hr/mL, respectively. The C_max and AUC_tau of the active metabolite, cidofovir diphosphate, were 9.7 pg/10⁶ cells and 1200 pg·hr/10⁶ cells, respectively. Maximum plasma concentrations (T_max) of brincidofovir are reached at approximately 3 hours post-administration, while maximal plasma concentrations for cidofovir diphosphate are reached at approximately 47 hours post-administration. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Brincidofovir is an important consideration for its dosing schedule: The mean terminal half-lives of brincidofovir and its pharmacologically active metabolite, cidofovir diphosphate, are 19.3 hours and 113 hours, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Brincidofovir exhibits a strong affinity for binding with plasma proteins: Brincidofovir is >99% protein-bound in plasma, although the specific protein(s) to which it binds have not been elucidated. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Brincidofovir from the body primarily occurs through: Brincidofovir is eliminated as metabolites in both the urine (~51%) and feces (~40%). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Brincidofovir is distributed throughout the body with a volume of distribution of: The apparent volume of distribution of brincidofovir is 1230 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Brincidofovir is a critical factor in determining its safe and effective dosage: The apparent clearance of brincidofovir in healthy adult patients is 44.1 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Brincidofovir exerts its therapeutic effects through: The pharmacologically active agent resulting from brincidofovir metabolism, cidofovir diphosphate, has an exceedingly long duration of action that allows for it to be dosed once weekly. The entirety of a brincidofovir smallpox treatment consists of only two doses, on days 1 and 8, which seemingly reduces the risk of adverse reactions. Regimens involving a longer duration of administration (i.e. more than a single dose on days 1 and 8) have been shown to increase mortality compared to placebo and should therefore be avoided. Brincidofovir is considered a potential human carcinogen and has demonstrated the potential to cause infertility - as such, its use should be restricted to situations in which it is absolutely necessary. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Brincidofovir functions by: Brincidofovir is a pro-drug comprising conjugated to a lipid molecule - the lipid component mimics an endogenous lipid, lysophosphatidylcholine, which allows the molecule to hijack endogenous lipid uptake pathways to enter infected cells. Following uptake, the lipid molecule is cleaved to generate cidofovir, which is then phosphorylated to generate the active antiviral compound, cidofovir disphosphate. The antiviral effects of cidofovir diphosphate appear to be the result of two distinct mechanisms. Mechanistic studies using recombinant vaccinia DNA polymerase suggest that it inhibits orthopoxvirus DNA polymerase-mediated DNA synthesis. In addition, cidofovir is an acyclic nucleotide analogue of deoxycytidine monophosphate - cidofovir diphosphate can therefore be incorporated into the growing viral DNA chain and consequently slow the rate of viral DNA synthesis. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Brincidofovir belongs to the class of organic compounds known as pyrimidones. These are compounds that contain a pyrimidine ring, which bears a ketone. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions, classified under the direct parent group Pyrimidones. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Diazines class, specifically within the Pyrimidines and pyrimidine derivatives subclass.

Categories:

Brincidofovir is categorized under the following therapeutic classes: Anti-Infective Agents, Antiinfectives for Systemic Use, Antiviral Agents, Antivirals for Systemic Use, BCRP/ABCG2 Inhibitors, BSEP/ABCB11 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (strength unknown), Cytochrome P-450 CYP2B6 Inhibitors, Cytochrome P-450 CYP2B6 Inhibitors (strength unknown), Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 inhibitors (strength unknown), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (strength unknown), Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C9 Inhibitors (strength unknown), Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (strength unknown), Cytochrome P-450 Enzyme Inhibitors, Cytomegalovirus Nucleoside Analog DNA Polymerase Inhibitor, Direct Acting Antivirals, Nucleosides and Nucleotides Excl. Reverse Transcriptase Inhibitors, OAT1/SLC22A6 inhibitors, OAT3/SLC22A8 Inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B1/SLCO1B1 Substrates, OATP1B3 substrates, Organophosphorus Compounds, Pyrimidines, Pyrimidinones. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Brincidofovir include:

• Water Solubility: Practically insoluble