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General Description:

Lefamulin, identified by CAS number 1061337-51-6, is a notable compound with significant therapeutic applications. Lefamulin is a pleuromutilin antibiotic used for the treatment of bacterial community-acquired pneumonia. A pleuromotilin is a more recently developed type of antibiotic that is derived from the fungus, Pleurotus mutilus. Lefamulin is available in intravenous and oral preparations and was granted FDA approval in August 2019. This drug is the first semi-synthetic pleuromutilin that has been designed for systemic administration. Lefamulin features a novel mechanism of action that shows benefit against resistant bacteria that cause pneumonia. The chemical structure of lefamulin contains a tricyclic mutilin core that is necessary for some of its antimicrobial activity.

Indications:

This drug is primarily indicated for: Lefamulin is indicated to treat adults diagnosed with community-acquired bacterial pneumonia (CABP) that is caused by susceptible bacteria. Its use should be reserved for confirmed susceptible organisms or a high probability of infection with susceptible organisms. The list of susceptible bacteria includes Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible), Legionella pneumophila, Haemophilus influenza, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lefamulin undergoes metabolic processing primarily in: CYP3A4 is the main enzyme responsible for the metabolism of lefamulin. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lefamulin are crucial for its therapeutic efficacy: In a pharmacokinetic study of healthy subjects, lefamulin was rapidly absorbed after oral administration. The median Tmax was measured at 1.00 h for the intravenous preparation and 1.76 h for the tablet preparation.At steady-state doses, the Cmax of oral lefamulin is 37.1 mcg/mL. The AUC at steady-state concentrations of this drug is 49.2 mcg·h/mL. The estimated bioavailability of the oral tablets is 25%. Clinical studies have found that the AUC of lefamulin is decreased by about 10-28% in the fed state. To optimize absorption, this drug should be administered a minimum of 1 hour before a meal or, at minimum, 2 hours after a meal with water. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lefamulin is an important consideration for its dosing schedule: The average elimination half-life of lefamulin is about 8 hours in patients diagnosed with community-acquired bacterial pneumonia. One pharmacokinetic study of healthy volunteers revealed a mean half-life of 13.2 hours after an intravenous infusion of lefamulin. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Lefamulin exhibits a strong affinity for binding with plasma proteins: The average plasma protein binding of lefamulin is between 94.8 to 97.1% in healthy adults. A systematic review identifies the plasma protein binding at 80-87%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Lefamulin from the body primarily occurs through: Lefamulin is largely excreted by the gastrointestinal tract and about 14% excreted by the kidneys. In healthy adult volunteers during clinical trials, a radiolabeled dose of lefamulin was administered. The total radioactivity found to be excreted in the feces was 77.3% on average with 4.2% to 9.1% as unchanged drug when the drug was administered via the intravenous route. A total radioactivity of 88.5% was measured in the feces with 7.8-24.8% as unchanged drug after a dose administered via the oral route. In the urine, it was found to be 15.5% with 9.6-14.1% excretd as unchanged drug after an intravenous dose and 5.3% after an oral dose. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lefamulin is distributed throughout the body with a volume of distribution of: The average volume of distribution of lefamulin is 86.1 L in patients with community-acquired bacterial pneumonia, but can range from 34.2 to 153 L. During clinical studies, lefamulin has been shown to significantly concentrate in the lung tissue, likely increasing its effectiveness in treating pneumonia. After lefamulin is administered, penetration into various tissues is observed, and is about 6 times greater in concentration in the fluid of the pulmonary epithelium, when compared with concentrations in the plasma. Animal studies demonstrate that lefamulin crosses the placenta. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Lefamulin is a critical factor in determining its safe and effective dosage: The total body clearance of lefamulin has been determined to range from 2.94 to 30.0 L/h after an injected dose. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Lefamulin exerts its therapeutic effects through: Lefamulin demonstrates strong antibacterial activity against several microbes that are found to be common in both acute bacterial skin and skin structure infections as well as community-acquired bacterial pneumonia. It shows antibacterial activity against gram-positive and atypical microbes (for example, Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae). Lefamulin also exerts activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. It does not treat Pseudomonas aeruginosa infections. During in vitro studies, drug has also has demonstrated activity against Neisseria gonorrhoeae and Mycoplasma genitalium. A note on QT prolongation and Clostridium difficile According to the FDA label, lefamulin may have cardiac QT interval prolonging effects and advises against the administration of this drug in patients with diagnosed QT prolongation or ventricular arrhythmias. The administration of lefamulin should also be avoided in patients being administered antiarrhythmic agents and other drugs that prolong the QT interval. As with other antibiotics, the risk of Clostridium difficile associated diarrhea is increased with lefamulin use. Any case of diarrhea should be evaluated for C. difficile. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lefamulin functions by: Lefamulin inhibits prokaryotic ribosomal protein synthesis via its binding to the peptidyl transferase center (PTC) of the ribosomal bacterial 50S subunit. It inhibits protein translation through binding to both the A and P sites of the PTC via four hydrogen bonds, resulting in the interruption of peptide bond formation. Lefamulin's tricyclic mutilin core is the common moiety for binding of all members of its drug class, the pleuromutilins. Although the tricyclic motilin core doesn’t form any hydrogen bonds with the PTC nucleotides, it is stabilized or anchored by hydrophobic and Van der Waals interactions. Lefamulin exerts a selective inhibition of protein translation in eukaryotes, however, does not affect ribosomal translation of eukaryotes. Lefamulin demonstrates a unique induced-fit type of action that closes the binding pocket within a ribosome, conferring close contact of the drug to its target, therefore improving therapeutic efficacy. Because of its mechanism of action that differs from that of other antimicrobials, cross-resistance to other antibiotic classes is less likely. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Lefamulin is categorized under the following therapeutic classes: Acetates, Anti-Bacterial Agents, Anti-Infective Agents, Antibacterials for Systemic Use, Antiinfectives for Systemic Use, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates (strength unknown), Cytochrome P-450 Substrates, P-glycoprotein substrates, Pleuromutilin Antibacterial, QTc Prolonging Agents, Sulfur Compounds. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Lefamulin include:

• Boiling Point: 618.6±55.0
• logP: 3.72
• pKa: 9.41