Pretomanid

Absorption

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.

Toxicity

To this date, there is no documented experience with the treatment of a pretomanid overdose. The FDA label advises that general supportive measures are taken to manage an overdose, such as monitoring vital signs in addition to performing ECG testing for a prolonged QT interval in the case of an overdose.

The Uses of Pretomanid

A novel anti-tuberculosis drug.

Background

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 Bedaquiline and Linezolid 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

Pretomanid is indicated, as part of a combination regimen with bedaquiline and linezolid, for the treatment of adults with pulmonary tuberculosis (TB) that is resistant to isoniazid, rifamycins, a fluoroquinolone and a second-line injectable antibacterial drug or adults with pulmonary TB resistant to isoniazid and rifampin, who are treatment-intolerant or non-responsive to standard therapy.

Biological Activity

pa-824, a bicyclic nitroimidazoles, is an anti-tuberculosis (tb) agent that exerts potent in vitro activity against mycobacterium tuberculosis with the minimal inhibition concentration (mic) ranging from 0.015 μg/ml to 0.25 μg/ml and remains actively against a wide range of isolates that are resistant to commonly used anti-tb agents leading to its successful application in the treatment of tb [1].pa-824 has been found to exhibit bactericidal activity against replicating bacilli and non-replicating bacilli under hypoxic or prolonged culture conditions in a dose dependent fashion through two possible mechanisms, which include pa-824 induced inhibition of ketomycolate synthesis and pa-824 mediated donation of nitric oxide during enzymatic nitro-reduction [1].

Biochem/physiol Actions

PA-824 is an anti-tuberculosis drug.

Pharmacokinetics

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.

Metabolism

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.

References

[1] ahmad z, peloquin ca, singh rp, derendorf h, tyagi s, ginsberg a, grosset jh, nuermberger el. pa-824 exhibits time-dependent activity in a murine model of tuberculosis. antimicrob agents chemother. 2011 jan;55(1):239-45. doi: 10.1128/aac.00849-10. epub 2010 oct 11.