PA 824

359.26

359.26

1533716-785-6

2XOI31YC4N

DTXSID8041163

J04|J - Antiinfectives for systemic use

91.3 Ų

2.75

1.58

149-150 °C

462.3±55.0 °C(Predicted)

<1 mg/mL

-0.67±0.40

7.0

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.

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.

The plasma protein binding of pretomanid is about 86.4%.

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.|Dovprela is indicated in combination with bedaquiline and linezolid, in adults, for the treatment of pulmonary extensively drug resistant (XDR), or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB).Consideration should be given to official guidance on the appropriate use of antibacterial agents.|Treatment of multi-drug-resistant tuberculosis

Pretomanid is a nitroimidazooxazine antimycobacterial agent used in combination with other antituberculosis drugs in the treatment of multidrug resistant tuberculosis. The addition of pretomanid to antituberculosis drug regimens has been linked to an increased rate of transient serum liver test abnormalities during treatment and to several instances of mild, clinically apparent liver injury.

Antituberculosis Agents

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.

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.|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.|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.|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.

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.

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.

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.

2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazine

Human drugs -> Orphan -> Dovprela (previously Pretomanid FGK) -> EMA Drug Category|Antimycobacterials -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients