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General Description:

Vaborbactam, identified by CAS number 1360457-46-0, is a notable compound with significant therapeutic applications. Vaborbactam is a β-lactamase inhibitor based on a cyclic boronic acid pharmacophore. It has been used in trials investigating the treatment of bacterial infections in subjects with varying degrees of renal insufficiency. In August 2017, a combination antibacterial therapy under the market name Vabomere was approved by the FDA for the treatment of adult patients with complicated urinary tract infections (cUTI). Vabomere consists of vaborbactam and for intravenous administration. Vaborbactam is added to the therapy to reduce the extent meropenem degradation by inhibiting the serine beta-lactamases expressed by the microorganism of target. The treatment aims to resolve infection-related symptoms of cUTI and achieve negative urine culture, when the infections are proven or strongly suspected to be caused by susceptible bacteria.

Indications:

This drug is primarily indicated for: Indicated in combination with meropenem for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: _Escherichia coli_, _Klebsiella pneumoniae_, and _Enterobacter cloacae_ species complex. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Vaborbactam undergoes metabolic processing primarily in: Vaborbactam does not undergo metabolism. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Vaborbactam are crucial for its therapeutic efficacy: The peak plasma concentrations (Cmax) and AUC of vaborbactam increase in a dose-proportional manner. In healthy adult subjects, the Cmax following administration of multiple 2 g dose as a 3-hour infusion was 55.6 mg/L and AUC was 588 mg•h/L. In patients with the same dosing regimen, the Cmax was 71.3 mg/L and AUC was 835 mg•h/L at steady state. The exposure of vaborbactam in terms of Cmax and AUC are not expected to change with repeated dosing, and there was no evidence of accumulation of vaborbactam in plasma in a repeated dosing study. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Vaborbactam is an important consideration for its dosing schedule: The half life of vaborbactam in healthy subjects following multiple 2 g dose administration as a 3-hour infusion was 1.68 hours. The half life of vaborbactam following administration of 2 g by 3 hour infusion was 2.25 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Vaborbactam exhibits a strong affinity for binding with plasma proteins: The average serum protein binding of vaborbactam is approximately 33%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Vaborbactam from the body primarily occurs through: Vaborbactam predominantly undergoes renal excretion, where about 75 to 95% of the dose is excreted unchanged in the urine over a 24 to 48 hour period. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Vaborbactam is distributed throughout the body with a volume of distribution of: The steady-state volume of distribution of vaborbactam in patients was 18.6 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Vaborbactam is a critical factor in determining its safe and effective dosage: The mean renal clearance for vaborbactam was 8.9 L/h. The mean non-renal clearance for vaborbactam was 2.0 L/h indicating nearly complete elimination of vaborbactam by the renal route. The clearance of vaborbactam in healthy subjects following administration of multiple doses of 2 g as a 3-hour infusion was 10.9 L/h. The clearance of vaborbactam in patients following administration of 2 g by 3 hour infusion was 7.95 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Vaborbactam exerts its therapeutic effects through: Vaborbactam shows no antibacterial activity alone; it serves to restore the antibacterial activity of other antibacterial agents such as meropenem by attenuating their degradation by inhibiting certain serine beta-lactamases of microorganisms. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms. Vaborbactam in combination with meropenem, which is a penem antibacterial drug, potentiates the bactericidal actions of meropenem against carbapenem-resistant KPC-containing _Escherichia coli_, _Klebsiella pneumoniae_, and _Enterobacter cloacae_ in a concentration-dependent manner. It restored the antimicrobial activity of meropenem in animal models of infection caused by some meropenem non-susceptible KPC-producing Enterobacteriaceae. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Vaborbactam functions by: Vaborbactam is a cyclic boronic acid pharmacophore β-lactamase inhibitor that elicits potent inhibition of _Klebsiella pneumoniae_ carbapenemase (KPC) enzymes and other Ambler class A and C enzymes such as serine β-lactamases that confer resistance to commonly-used antibiotics such as Carbapenems. Vaborbactam is a potent inhibitor of class A carbapenemases, such as KPC, as well as an inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) beta-lactamases. Vaborbactam interacts with β-lactamases of Ambler classes A and C via precovalent and covalent binding. It exerts no inhibitory actions on class D or class B carbapenemases. The production of contemporary β-lactamase by bacterial isolates potentiate the degradation of β-lactam antibiotic agents, rendering them clinically ineffective and posing challenges for patients receiving the standard antibiotic therapy. In combination with meropenem, varborbactam acts as a non-suicidal beta-lactamase inhibitor that protects meropenem from degradation mediated by serine beta-lactamases such as _Klebsiella pneumoniae_ carbapenemase (KPC). This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Vaborbactam belongs to the class of organic compounds known as oxaborine derivatives. These are compounds containing a six-member aliphatic heterocycle made up of one oxygen atom, a boron atom, and three carbon atoms, classified under the direct parent group Oxaborine derivatives. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Metalloheterocyclic compounds class, specifically within the Oxaborine derivatives subclass.

Categories:

Vaborbactam is categorized under the following therapeutic classes: Acids, Acids, Noncarboxylic, Anti-Infective Agents, Antibacterials for Systemic Use, Antiinfectives for Systemic Use, beta-Lactamase Inhibitors, Boron Compounds, Drugs that are Mainly Renally Excreted, Enzyme Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.