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Plazomicin API Manufacturers & Suppliers

General Description:

Plazomicin, identified by CAS number 1154757-24-0, is a notable compound with significant therapeutic applications. Developed by Achaogen biopharmaceuticals, plazomicin is a next-generation aminoglycoside synthetically derived from . The structure of plazomicin was established via appending hydroxylaminobutyric acid to at position 1 and 2-hydroxyethyl group at position 6' . It was designed to evade all clinically relevant aminoglycoside-modifying enzymes, which contribute to the main resistance mechanism for aminoglycoside therapy . However, acquired resistance of aminoglycosides may arise through over expression of efflux pumps and ribosomal modification by bacteria, which results from amino acid or rRNA sequence mutations . Like other aminoglycosides, plazomicin is ineffective against bacterial isolates that produce 16S rRNA methyltransferases . Plazomicin mediates the antibacterial activity against pathogens including carbapenem-resistant (CRE) and extended-spectrum beta-lactamase (ESBL) producing _Enterobacteriaceae_. It mediates the antibacterial activity by binding to bacterial 30S ribosomal subunit and inhibiting protein synthesis . On June 28th, 2018, plazomicin sulfate was approved by the FDA for use in adult patients for the treatment of complicated urinary tract infections (cUTI) including Pyelonephritis. It is marketed as Zemdri and is administered via once-daily intravenous infusion.

Indications:

This drug is primarily indicated for: Plazomicin is indicated for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis, who have limited or no alternative treatment options. It should only be used to treat infections that are proven or strongly suspected to be caused by susceptible microorganisms . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

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

Absorption:

The absorption characteristics of Plazomicin are crucial for its therapeutic efficacy: Administration of 15 mg/kg plazomicin by 30-minute IV infusion resulted in peak plasma concentrations of 73.7 ± 19.7 μg/mL in healthy adult subjects and 51.0 ± 26.7 μg/mL in patients with complicated urinary tract infections (cUTI) . The area under the curve (AUC) were 257 ± 67.0 μg.h/mL in healthy adults and 226 ± 113 μg.h/mL in cUTI patients . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Plazomicin is an important consideration for its dosing schedule: The mean (±SD) half-life of plazomicin was 3.5 h (±0.5) in healthy adults with normal renal function receiving 15 mg/kg plazomicin via intravenous infusion . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Plazomicin exhibits a strong affinity for binding with plasma proteins: The extent of plasma protein binding in humans is approximately 20% . The degree of protein binding was concentration-independent across the range tested in vitro (5 to 100 mcg/mL) . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Plazomicin from the body primarily occurs through: Plazomicin predominantly undergoes renal excretion, where 56% of the total administered drug was recovered in the urine within 4 hours following a single 15 mg/kg IV dose of radiolabeled plazomicin in healthy subjects. About less than 0.2% and 89.1% of the total drug were recovered within 168 hours in feces and urine, respectively . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Plazomicin is distributed throughout the body with a volume of distribution of: The mean (±SD) volume of distribution is 17.9 (±4.8) L in healthy adults and 30.8 (±12.1) L in cUTI patients . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Plazomicin is a critical factor in determining its safe and effective dosage: Following administration of 15 mg/kg plazomicin by 30-minute IV infusion, the mean (±SD) total body clearance in healthy adults and cUTI patients is 4.5 (±0.9) and 5.1 (±2.01) L/h, respectively . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Plazomicin exerts its therapeutic effects through: Plazomicin exerts its antibacterial activity in a dose-dependent manner with a post-antibiotic effect ranging from 0.2 to 2.6 hours at 2X MIC against _Enterobacteriaceae_, as demonstrated by _in vitro_ studies . In clinical trials comprising of hospitalized adult patients with cUTI (including pyelonephritis), resolution or improvement of clinical cUTI symptoms and a microbiological outcome of eradication were observed at day 5 following the first dose administration of plazomicin . Plazomicin has shown to elicit nephrotoxic, ototoxic, and neuromuscular blocking effects. In clinical trials, it did not induce any clinically relevant QTc-prolonging effects . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Plazomicin functions by: Plazomicin exerts a bactericidal action against susceptible bacteria by binding to bacterial 30S ribosomal subunit . Aminoglycosides typically bind to the ribosomal aminoacyl-tRNA site (A-site) and induce a conformational change to further facilitate the binding between the rRNA and the antibiotic . This leads to codon misreading and mistranslation of mRNA during bacterial protein synthesis . Plazomicin demonstrates potency against _Enterobacteriaceae_, including species with multidrug-resistant phenotypes such as carbapenemase-producing bacteria and isolates with resistance to all other aminoglycosides . Its antibacterial activity is not inhibited by aminoglycoside modifying enzymes (AMEs) produced by bacteria, such as acetyltransferases (AACs), phosphotransferases (APHs), and nucleotidyltransferases (ANTs) . Plazomicin was shown to be effective against _Enterobacteriaceae_ in presence of some beta-lactamases . In clinical settings and _in vivo_, bacteria shown to be susceptible toward plazomicin include _Escherichia_ _coli_, _Klebsiella pneumoniae_, _Proteus mirabilis_, and _Enterobacter cloacae_ . Other aerobic bacteria that may be affected by plazomicin are _Citrobacter freundii_, _Citrobacter koseri_, _Enterobacter aerogenes_, _Klebsiella oxytoca_, _Morganella morganii_, _Proteus vulgaris_, _Providencia stuartii_, and _Serratia marcescens_ . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Plazomicin belongs to the class of organic compounds known as gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom, classified under the direct parent group Gamma amino acids and derivatives. This compound is a part of the Organic compounds, falling under the Organic acids and derivatives superclass, and categorized within the Carboxylic acids and derivatives class, specifically within the Amino acids, peptides, and analogues subclass.

Categories:

Plazomicin is categorized under the following therapeutic classes: Agents that produce neuromuscular block (indirect), Aminoglycoside Antibacterials, Anti-Bacterial Agents, Antibacterials for Systemic Use, Antiinfectives for Systemic Use, Carbohydrates, Drugs that are Mainly Renally Excreted, Drugs that are Mainly Renally Excreted with a Narrow Therapeutic Index, Gentamicins, Glycosides, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE inhibitors, Narrow Therapeutic Index Drugs, Nephrotoxic agents. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.