PRETOMANID 200 mg PD

Indications

• Multidrug-resistant tuberculosis (MDR-TB)
• Extensively drug-resistant tuberculosis (XDR-TB)
• Pulmonary tuberculosis

Dosage

Children: Refer to the BNF for Children for appropriate dosing recommendations.

Adults: Refer to the BNF for appropriate dosing recommendations.

Mechanism of action

Pretomanid is activated by the nitroreductase enzyme Ddn, leading to the production of active metabolites, including a des-nitro derivative. This derivative increases nitric oxide levels, which acts as a bacterial respiratory poison, particularly effective under anaerobic conditions. Additionally, pretomanid inhibits mycolic acid biosynthesis in the bacterial cell wall, targeting actively replicating Mycobacterium tuberculosis and contributing to the drug's bactericidal activity.

Pharmacodynamics

Pretomanid has demonstrated the ability to kill actively replicating Mycobacterium tuberculosis, significantly reducing pulmonary bacterial counts in animal models. In clinical settings, when used in combination with bedaquiline and linezolid, pretomanid has shown a high cure rate of approximately 90% in patients with XDR and MDR-TB after six months. However, it is associated with potential adverse effects such as QT interval prolongation, hepatotoxicity, and myelosuppression, necessitating careful monitoring during treatment.

Pharmacokinetics

Pretomanid has a molecular formula of C14H12F3N3O5. The pharmacokinetic profile, including its absorption, distribution, metabolism, and excretion, remains to be fully elucidated, but its activation relies on metabolic processes involving nitroreductase enzymes. Caution is advised due to its potential for hepatic metabolism and clearance issues.

Contra-indications

• Severe hepatic impairment
• History of hypersensitivity to pretomanid or any of its components

Adverse effects

• Cardiac QT interval prolongation
• Hepatotoxicity
• Myelosuppression
• Nausea
• Vomiting
• Headache
• Fatigue

Interactions

• Caution with other drugs that prolong the QT interval
• Potential interactions with hepatotoxic drugs
• May alter the effects of antiretroviral therapies

Precautions

• Monitor liver function tests regularly
• Assess QT interval prior to and during treatment
• Use with caution in patients with a history of cardiac arrhythmias
• Consider the potential for drug-drug interactions

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Pretomanid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known if pretomanid is excreted in human milk. Caution should be exercised when administering to a nursing mother.

Storage

Store at room temperature, away from moisture and light. Keep out of reach of children.

Formulations

• Pretomanid 200 mg tablet

Mechanism of action

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.

Pharmacodynamics

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.