Pretomanid API Manufacturers

General Description:

Pretomanid, identified by CAS number 187235-37-6, is a notable compound with significant therapeutic applications. Persistent forms of tuberculosis (TB) have proven to be a major cause of global morbidity and mortality and a cause for significant concern. Research in recent years has been geared toward the development of novel therapies that target persistent forms of this disease, which have shown resistance to standard therapy regimens. Pretomanid is an antimycobacterial agent that is administered with and to treat resistant forms of pulmonary TB. It was the first TB drug developed by a nonprofit organization, known as TB Alliance, and was granted FDA approval on August 14, 2019. Unlike other therapeutic regimens for the treatment of resistant TB, which may take 18 months or longer and may not be effective, the pretomanid-containing regimen allows for a more efficacious and shorter duration of treatment with fewer drugs.

Indications:

This drug is primarily indicated for: Pretomanid is indicated for adults in combination with bedaquiline and linezolid for the treatment of pulmonary forms of nonresponsive multidrug-resistant (MDR), extensively drug-resistant (XDR), and treatment-intolerant forms of pulmonary tuberculosis (TB). It is important to note that the following conditions are not approved indications for pretomanid therapy, according to the FDA: Drug-sensitive (DS) tuberculosis, latent tuberculosis caused by M.tuberculosis, extra-pulmonary tuberculosis caused by M.tuberculosis, and multidrug-resistant TB that is not treatment-intolerant or nonresponsive to conventional TB therapy. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Pretomanid undergoes metabolic processing primarily in: Various reductive and oxidative pathways are responsible for pretomanid metabolism, with no single major metabolic pathway identified. According to in vitro studies, CYP3A4 is responsible for a 20% contribution to the metabolism of pretomanid. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Pretomanid are crucial for its therapeutic efficacy: This drug is absorbed in the gastrointestinal tract. The steady-state Cmax of pretomanid was estimated to be 1.7 μg/mL after a single 200mg oral dose. In a separate pharmacokinetic modeling study, the Cmax of a 200mg dose was 1.1 μg/ml. Tmax in a study of healthy subjects in the fed or unfed state was achieved within 4 to 5 hours. The AUC in the same study was found to be about 28.1 μg•hr/mL in the fasted state and about 51.6 μg•hr/mL in the fed state, showing higher absorption when taken with high-calorie and high-fat food. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Pretomanid is an important consideration for its dosing schedule: The elimination half-life was determined to be 16.9-17.4 hours in a pharmacokinetic study of healthy subjects. An FDA briefing document reports a half-life of 18 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Pretomanid exhibits a strong affinity for binding with plasma proteins: The plasma protein binding of pretomanid is about 86.4%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Pretomanid from the body primarily occurs through: Healthy adult male volunteers were administered a 1,100 mg oral dose of radiolabeled pretomanid in one pharmacokinetic study. An average of about 53% of the radioactive dose was found to be excreted in the urine. Approximately 38% was measured mainly as metabolites in the feces. A estimated 1% of the radiolabeled dose was measured as unchanged drug in the urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Pretomanid is distributed throughout the body with a volume of distribution of: A pharmacokinetic modeling study estimated the volume of distribution at 130 ± 5L. A pharmacokinetic study in healthy volunteers determined a volume of distribution of about 180 ± 51.3L in fasted state and 97.0 ± 17.2L in the fed state. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Pretomanid is a critical factor in determining its safe and effective dosage: The clearance of pretomanid in a pharmacokinetic simulation study has been estimated at 4.8 ± 0.2 liters/h. According to the FDA label, the clearance of a single 200 mg oral dose of pretomanid is estimated to be 7.6 liters/h in the fasted state, and 3.9 liters/h in the fed state. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Pretomanid exerts its therapeutic effects through: Pretomanid kills the actively replicating bacteria causing tuberculosis, known as Mycobacterium tuberculosis, and shortens the duration of treatment in patients who suffer from resistant forms of pulmonary TB by killing dormant bacteria. In rodent models of tuberculosis infection, pretomanid administered in a regimen with bedaquiline and linezolid caused a significant reduction in pulmonary bacterial cell counts. A decrease in the frequency of TB relapses at 2 and 3 months after treatment was observed after the administration of this regimen, when compared to the administration of a 2-drug regimen. Successful outcomes have been recorded for patients with XDR and MDR following a clinical trial of the pretomanid regimen, demonstrating a 90% cure rate after 6 months. A note on cardiac QT prolongation, hepatotoxicity, and myelosuppression This drug has the propensity to caused cardiac QT interval prolongation and significant hepatotoxicity, as well as myelosuppression. Caution must be observed during the administration of this drug. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Pretomanid functions by: Pretomanid is a prodrug which is metabolically activated by a nitroreductase enzyme, known as Ddn, producing various active metabolites that are responsible for its other therapeutic actions, particularly the induction of nitric oxide. The nitroreductase enzyme which activates pretomanid is deazaflavin dependent and relies on reduced cofactor F420. Reduction of F420 occurs via the enzyme glucose-6-phosphate dehydrogenase. Reduction of pretomanid's imidazole ring at the C-3 position causes the formation of the metabolites, which include a des-nitro derivative. The formation of this derivative leads to increased levels of nitric oxide, leading to bactericidal activities under anaerobic conditions via its action as a bacterial respiratory poison. Bactericidal activity against anaerobes is reported to be associated with a shortened duration of antibiotic treatment. Pretomanid exerts aerobic bactericidal effects through its inhibitory actions on bacterial cell wall mycolic acid biosynthesis. This allows for the killing of actively replicating Mycobacterium tuberculosis bacteria, resulting in the treatment of active tuberculosis infection. The molecular mechanism of the above bactericidal effects is poorly understood at this time, but may involve effects exerted on various genes that affect the cell wall, including the fasI and fasII as well as the efpA and iniBAC operons. Other possible targets include the genes of the cyd operon. The clinical effects of the above target relations are unknown at this time. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Pretomanid belongs to the class of organic compounds known as benzylethers. These are aromatic ethers with the general formula ROCR' (R = alkyl, aryl; R'=benzene), classified under the direct parent group Benzylethers. 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 Benzylethers subclass.

Categories:

Pretomanid is categorized under the following therapeutic classes: Antiinfectives for Systemic Use, Antimycobacterials, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates (strength unknown), Cytochrome P-450 Substrates, Drugs for Treatment of Tuberculosis, Imidazoles, Nitro Compounds, OAT3/SLC22A8 Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Pretomanid include:

• Water Solubility:<1 mg/mL
• Boiling Point: 462.3±55.0
• logP: 2.75
• caco2 Permeability: 27.6
• pKa: 7.0