Delamanid

Delamanid is a nitroimidazole used for multidrug-resistant tuberculosis within longer individualised regimens when bedaquiline cannot be used. It prolongs the QT interval modestly and has fewer clinically important interactions than the rifamycins. Availability depends on national programmes.

Class. Nitro-dihydro-imidazooxazole antimycobacterial.

Mechanism. A prodrug activated by the bacterial deazaflavin-dependent nitroreductase (Ddn), which blocks synthesis of methoxy- and keto-mycolic acids and releases reactive nitrogen species. Cross-resistance occurs with pretomanid.

Pharmacokinetics. Absorption rises with food, peak at 4 to 5 hours, highly protein bound (over 99.5%), half life 30 to 38 hours. Metabolised mainly by albumin to DM-6705, which is further metabolised by CYP3A4; the DM-6705 metabolite prolongs QT.

Multidrug-resistant tuberculosis (adults and children 3 years and over). - Adults and children 35 kg or over: 100 mg orally twice daily for 24 weeks. - Children 20 to 34 kg: 50 mg twice daily; 10 to 19 kg: 25 mg twice daily (dispersible tablet), by weight band. - Alternative: 200 mg once daily in adults is used by some programmes. - Loading dose: none. Maintenance dose: the same twice-daily dose through the 24 weeks. Maximum adult dose: 200 mg daily. - Duration: 24 weeks; extended courses are used in selected patients.

Role. Used when bedaquiline cannot be used, or sequentially to complete longer regimens. Use of delamanid with bedaquiline is specialist-only.

Titration. None; interrupt for QT prolongation.

Contraindications. Serum albumin under 2.8 g/dL (28 g/L), QT prolongation, uncorrected electrolyte abnormality, and hypersensitivity.

Serious adverse effects. QT prolongation, arrhythmia, hepatotoxicity, anxiety and psychosis (rare).

Common adverse effects. Nausea, vomiting, headache, dizziness, insomnia, paraesthesia and palpitations.

Interactions. - Avoid strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, efavirenz). - Avoid strong CYP3A4 inhibitors where possible. - Additive QT prolongation with fluoroquinolones, clofazimine, bedaquiline, macrolides and antipsychotics.

Common prescribing errors. Skipping baseline albumin and ECG, giving it fasting, and combining multiple QT-prolonging drugs without ECG surveillance.

Special groups. - Pregnancy: limited data; use only when no alternative. - Breastfeeding: limited data; infant exposure occurs. - Children: dosed by weight from age 3 years. - Older adults: monitor ECG and albumin. - Kidney impairment: no adjustment in mild to moderate; not advised in severe disease. - Liver impairment: caution in moderate; avoid in severe.

Formulations. Tablets 50 mg and dispersible tablets 25 mg.

Administration. With a meal, twice daily about 12 hours apart.

Baseline. ECG with QTcF, potassium, calcium, magnesium, albumin and liver tests.

Monitoring. ECG at baseline, 2, 4, 8, 12 and 24 weeks; electrolytes and albumin monthly; liver tests monthly.

Stopping thresholds. Stop for QTcF over 500 ms (confirmed), arrhythmia, albumin falling under 2.8 g/dL with QT prolongation, or hepatitis.

Referral and escalation. Manage within a drug-resistant tuberculosis programme; cardiology for syncope or ventricular arrhythmia.