DEMTIBI

Indications

• Multidrug-resistant pulmonary tuberculosis
• Combination therapy with other antituberculosis drugs

Dosage

Children: 20 mg/kg once daily for 2 months (

Adults: 100 mg twice daily for 24 weeks, continuing appropriate combination therapy.

Mechanism of action

Delamanid is a prodrug that is biotransformed via the mycobacterial F420 coenzyme system, particularly by the deazaflavin-dependent nitroreductase (Rv3547), to exert its antimycobacterial activity. The activated form inhibits the synthesis of methoxy-mycolic and keto-mycolic acids, essential components of the mycobacterial cell wall, resulting in cell wall depletion and bacterial destruction. Resistance may occur through mutations in F420 coenzyme genes.

Pharmacodynamics

Delamanid exhibits minimum inhibitory concentrations (MIC) against Mycobacterium tuberculosis ranging from 0.006 to 0.024 g/mL. It has demonstrated in vitro activity against non-tuberculous mycobacteria such as M. kansasii and M. bovis, but shows no activity against Gram-positive or Gram-negative bacteria. In murine models, delamanid reduces M. tuberculosis colony counts in a dose-dependent manner. It may cause QTc prolongation and has effects on vitamin K-dependent blood clotting, increasing prothrombin time and activated partial thromboplastin time.

Pharmacokinetics

Delamanid is absorbed following oral administration, with its pharmacokinetics influenced by food intake. It is metabolized in the liver, with its main metabolite being DM-6705. The elimination half-life of delamanid is around 30 hours. It is primarily excreted in urine as metabolites, with minimal unchanged drug in urine. Renal impairment may necessitate dosage adjustments due to altered clearance.

Contra-indications

• Optic neuritis
• Moderate to severe hepatic impairment
• Severe renal impairment

Adverse effects

• Anxiety
• Appetite decreased
• Asthenia
• Chest pain
• Cough
• Depression
• Dyslipidaemia
• Dyspnoea
• Ear pain
• Electrolyte imbalance
• Gastrointestinal discomfort
• Haemoptysis
• Headache
• Hyperhidrosis
• Hypertension
• Hypotension
• Malaise
• Muscle weakness
• Nausea
• Oropharyngeal pain

Interactions

• Mitotane - Severe (decreases exposure)
• Rifampicin - Severe (decreases exposure)
• Cobicistat - Unknown (increases exposure)
• Idelalisib - Unknown (increases exposure)
• Clarithromycin - Unknown (increases exposure)

Precautions

• Risk factors for QT interval prolongation (e.g. electrolyte disturbances, acute myocardial infarction, heart failure with reduced left ventricular ejection fraction, severe hypertension, left ventricular hypertrophy, bradycardia, congenital long QT syndrome, history of symptomatic arrhythmias)
• Use with caution in elderly and young children

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk-crosses the placenta.

Breast-feeding

Manufacturer advises avoid-present in milk in animal studies, but amount too small to be harmful.

Storage

Dispense in original container (contains desiccant).

Formulations

• Delamanid 50 mg tablet
• Deltyba 50 mg tablet

Mechanism of action

Delamanid is a prodrug that requires biotransformation via via the mycobacterial F420 coenzyme system, including the deazaflavin dependent nitroreductase (Rv3547), to mediate its antimycobacterial activity against both growing and nongrowing mycobacteria. Mutations in one of five coenzyme F420 genes, _fgd, Rv3547, fbiA, fbiB, and fbiC_ has been proposed as the mechanism of resistance to delamanid. Upon activation, the radical intermediate formed between delamanid and desnitro-imidazooxazole derivative is thought to mediate antimycobacterial actions via inhibition of methoxy-mycolic and keto-mycolic acid synthesis, leading to depletion of mycobacterial cell wall components and destruction of the mycobacteria. Nitroimidazooxazole derivative is thought to generate reactive nitrogen species, including nitrogen oxide (NO). However unlike isoniazid, delamanid does not alpha-mycolic acid.

Pharmacodynamics

The minimum inhibitory concentrations (MIC) of delamanid against _Mycobacterium tuberculosis_ isolates ranges from 0.006 to 0.024 g/mL. Among non-tuberculosis mycobacteria, delamanid has _in vitro_ activity against _M. kansasii_ and _M. bovis_. Delamanid has no in vitro activity against Gram negative or positive bacterial species and does not display cross-resistance to other anti-tuberculosis drugs. In murine models of chronic tuberculosis, the reduction of _M. tuberculosis_ colony counts by delamanid was demonstrated in a dose-dependent manner. Repeated dosing of delamanid may cause QTc-prolongation via inhibition of cardiac potassium channel (hERG channel), and this effect is mostly contributed by the main metabolite of delamanid, DM-6705. Animal studies indicate that delamanid may attenuate vitamin K-dependent blood clotting, increase prothrombin time (PT), and activated partial thromboplastin time (APTT).