Pretomanid
Pretomanid Uses, Dosage, Side Effects, Food Interaction and all others data.
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.
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.
| Trade Name | Pretomanid |
| Availability | Prescription only |
| Generic | Pretomanid |
| Pretomanid Other Names | Pretomanid |
| Related Drugs | bedaquiline, aminosalicylic acid, Paser, Sirturo |
| Weight | 200mg |
| Type | Oral tablet |
| Formula | C14H12F3N3O5 |
| Weight | Average: 359.2574 Monoisotopic: 359.072905124 |
| Protein binding | The plasma protein binding of pretomanid is about 86.4%. |
| Groups | Approved |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Pretomanid is part of a three-drug regimen used for the treatment of extensively drug-resistant and multidrug-resistant pulmonary tuberculosis.
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.
Pretomanid is also used to associated treatment for these conditions: Nonresponsive pulmonary multidrug-resistant (MDR) tuberculosis (TB), Pulmonary extensively drug resistant (XDR) tuberculosis (TB), Treatment-intolerant pulmonary TB (tuberculosis), Tuberculosis (TB)
How Pretomanid works
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.
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.
Food Interaction
- Avoid alcohol. Consuming alcohol may increase the risk of hepatotoxicity.
- Take with food.
[Moderate] ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of pretomanid.
The mechanism has not been reported.
Compared with the fasted state, oral administration of pretomanid with a high-fat, high-calorie meal (approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) increased mean systemic exposure (AUC) and peak plasma concentration (Cmax) of pretomanid by 88% and 76%, respectively.
MANAGEMENT: To ensure maximal oral absorption, pretomanid should be administered with food.
Tablets should be swallowed whole.
Pretomanid Drug Interaction
Moderate: somatropinUnknown: fentanyl, iobenguane I 131, timolol, bosutinib, benzocaine / dextromethorphan / menthol, carvedilol, phenoxybenzamine, rilpivirine, risdiplam, givosiran, antihemophilic factor, zalcitabine, etonogestrel, tolvaptan, lutetium lu 177 dotatate, filgrastim, isoniazid, aminosalicylic acid, fluoxetine
Pretomanid Disease Interaction
Volume of Distribution
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.
Elimination Route
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.
Half Life
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.
Clearance
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.
Elimination Route
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.
Innovators Monograph
You find simplified version here Pretomanid
