Pretomanid

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Anti infectives for systemic use -> Antibacterials for systemic use

Breast Feeding; Lactation; Milk, Human; Anti-infective Agents; Antitubercular Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine (Orphan designations)

FDA approved drugs -> Active ingredient

Antituberculosis medicines

Warning

H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]

P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

Liver test abnormalities occur in 30% of patients treated with multiple drug regimens that include pretomanid. These abnormalities are usually asymptomatic, mild-to-moderate in severity and self-limited in duration. In many instances, it is difficult to determine which of the antituberculosis medications account for the abnormalities, but regular monitoring of liver tests is recommended during triple therapy with pretomanid, bedaquiline and linezolid. Clinically apparent liver injury has been reported with pretomanid-based therapies, but largely in regimens that included moxifloxacin or pyrazinamide or both. The clinical features, course and outcome of these cases has not been well defined. In the pivotal study of pretomanid combined with bedaquiline and linezolid in 109 adults with drug resistant pulmonary tuberculosis, 12 patients (11%) developed ALT levels above 3 times the upper limit of normal (ULN) of whom two also developed mild jaundice (bilirubin above twice but less than 3 times ULN) arising during month two of therapy. Both patients had mild nausea accompanying the liver test abnormalities, and the abnormalities resolved in both with temporary interruption in treatment, followed by re-initiation using lower dose linezolid without change in the pretomanid dose. In this pivotal trial, most adverse events were attributed to linezolid.

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

J04AK08

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.

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.