Pretomanid

Pretomanid is a nitroimidazooxazine used only in combination, mainly with bedaquiline and linezolid, for 6-month regimens for highly drug-resistant tuberculosis. It is not used alone. Its main safety issues are hepatotoxicity, neuropathy and myelosuppression, which largely come from companion drugs.

Class. Nitroimidazooxazine antimycobacterial.

Mechanism. A prodrug activated by Ddn nitroreductase. It inhibits mycolic acid synthesis in replicating bacilli and releases nitric oxide in non-replicating bacilli. Cross-resistance occurs with delamanid.

Pharmacokinetics. Absorption rises with food, peak at about 4 to 5 hours, half life about 16 to 18 hours, extensive hepatic metabolism including CYP3A4, and excretion in urine and faeces.

Pre-extensively drug-resistant or extensively drug-resistant tuberculosis, or multidrug-resistant disease with intolerance of other regimens (adults).

• Pretomanid 200 mg orally once daily with food
• Combined with bedaquiline (400 mg daily for 2 weeks, then 200 mg three times weekly) and linezolid 600 mg daily for 26 weeks
• Loading dose: none
• Maximum: 200 mg daily

Rifampicin-resistant disease with fluoroquinolone susceptibility. Moxifloxacin 400 mg daily is added for 6 months in some regimens; pretomanid dose is unchanged.

Titration. Reduce or interrupt linezolid for toxicity; pretomanid dose is not adjusted.

Children. Not established; not used routinely.

Contraindications. Hypersensitivity, and any contraindication to partner drugs.

Serious adverse effects. Hepatotoxicity, peripheral and optic neuropathy, myelosuppression and lactic acidosis (mostly from linezolid), QT prolongation, hyperamylasaemia, and raised creatinine without true kidney injury because tubular secretion is inhibited. Animal data show testicular toxicity; male fertility effects are not established.

Common adverse effects. Nausea, vomiting, headache, rash and raised transaminases.

Interactions. - Avoid strong CYP3A4 inducers such as rifampicin and efavirenz. - Avoid strong CYP3A4 inhibitors where possible. - Possible effects on OAT3 substrates. - Additive QT and toxicity risks with partner drugs.

Common prescribing errors. Omitting food, using it as a single agent, ignoring linezolid toxicity and interpreting rises in creatinine as kidney failure.

Special groups.

• Pregnancy: limited data; use only when the benefit outweighs risk
• Breastfeeding: limited data; infant exposure possible
• Children: not established
• Older adults: monitor liver tests and counts
• Kidney impairment: mild to moderate no adjustment; severe disease has limited data
• Liver impairment: caution; monitor liver tests

Formulations. Tablets 200 mg.

Administration. Once daily with food.

Baseline. Liver tests, full blood count, creatinine, ECG, visual acuity and colour vision, pregnancy test.

Monitoring. Liver tests monthly or more often; full blood count weekly in the first month and monthly thereafter; ECG at baseline, 2, 4, 8, 12 and 24 weeks; vision and neuropathy at each visit.

Stopping thresholds. Stop for ALT over three times the upper limit of normal with symptoms, or over five times without; stop each partner drug when its own toxicity threshold is reached.

Referral and escalation. Manage within a drug-resistant tuberculosis programme.