Delamanid

Common name: Delamanid
Trade name: Deltyba
All names: Delamanid, Delba, Deltyba, Delamanid

Indications:
Deltyba is indicated for use in appropriate combination regimens in adult patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) when an effective treatment regimen cannot be composed due to drug resistance or tolerance. Official guidance on the appropriate use of antimicrobials should be considered.

Usage and dosage:
Adults: The recommended dose is 100 mg twice daily for 24 weeks.

Adverse reactions:
The most common adverse drug reactions (ie, incidence> in patients treated with delamanid + optimized background regimen (OBR) 10%): nausea, vomiting, headache, insomnia, dizziness, tinnitus, hypokalemia, gastritis, decreased appetite and weakness.

Taboos:
Allergy to any excipient of the active substance.
Serum albumin<2.8 g / dL
Taking drugs that are strong inducers of CYP3A4 (such as carbamazepine).

Notes:
QT prolongation has been observed in patients treated with delamanid. This prolongation slowly increases over time during the first 6-10 weeks of treatment and remains stable thereafter. QTc prolongation is closely related to the major delamanid metabolite DM-6705. Plasma albumin and CYP3A4 regulate the formation and metabolism of DM-6705, respectively.
An electrocardiogram (ECG) is recommended before starting treatment and monthly throughout the course of treatment with delamanid. If QTcF >500 ms is observed before the first dose of delamanid or during delamanid therapy, delamanid therapy should not be initiated or treatment should be discontinued. If the QTc interval duration exceeds 450/470 ms in male/female patients during delamanid therapy, these patients should undergo more frequent ECG monitoring. It is also recommended that serum electrolytes, such as potassium, be obtained at baseline and corrected if abnormal.
Hypoalbuminemia: In a clinical study, the presence of hypoalbuminemia was associated with an increased risk of QTc interval prolongation in patients treated with delamanid. Delamanid is contraindicated in patients with albumin <2.8 g/dL. Patients who are initiated on delamanid with a serum albumin <3.4 g/dL or whose serum albumin falls to this range during treatment should receive very frequent ECG monitoring throughout delamanid treatment.
Coadministration with Strong CYP3A4 Inhibitors: Coadministration of pyrimidines with strong CYP3A4 inhibitors (lopinavir/ritonavir) is associated with a 30% increase in exposure to the metabolite DM-6705, which is associated with QTc prolongation. Therefore, if coadministration of delamanid with any strong CYP3A4 inhibitor is deemed necessary, very frequent ECG monitoring is recommended throughout delamanid treatment.
Coadministration with Fluoroquinolones: All QTcF prolongations greater than 60 msec were associated with concomitant fluoroquinolone use. Therefore, if coadministration is considered unavoidable in order to construct an appropriate MDR-TB treatment regimen, very frequent ECG monitoring throughout delamanid treatment is recommended.

Storage:
Save at room temperature and avoid light.

Mechanism of action:
Deltyba is a nitrodihydroimidazooxazole derivative with a novel mechanism of action. The drug inhibits the synthesis of mycolic acid (an important component of the outer waxy shell of Mycobacterium tuberculosis, which helps the bacteria resist penicillin and most other antibiotics), interferes with Mycobacterium tuberculosis (MTB) cell wall metabolism, and thereby inhibits the activity against drug-resistant strains.

Safety and efficacy:
A randomized, placebo-controlled trial of 481 patients with pulmonary multidrug-resistant tuberculosis showed that adding 100 mg of delamanid twice daily to background therapy improved the 2-month sputum culture conversion rate (assessed in liquid broth medium) to 45.4%, compared with 29.6% with placebo (p=0.008).
In an observational follow-up study of 421 participants, Patients treated with delamanid for ≥6 months had a significantly higher rate of favorable outcome (cure or treatment completion) at 24 months than those treated for ≤2 months (74.5% vs 55%; RR 1.35 [95% CI 1.17–1.56], p <0.001). Mortality was also significantly lower with extended treatment (1.0% vs 8.3%, p < 0.001).