Delamanid

Delamanid Uses, Dosage, Side Effects, Food Interaction and all others data.

Delamanid is an anti-tuberculosis agent derived from the nitro-dihydro-imidazooxazole class of compounds that inhibits mycolic acid synthesis of bacterial cell wall . It is used in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis (TB) in a combination regimen. Emergence of multidrug-resistant and extensively drug-resistant tuberculosis creates clinical challenges for patients, as the disease is associated with a higher mortality rate and insufficient therapeutic response to standardized antituberculosis treatments as Isoniazid and Rifampicin. Multidrug-resistant tuberculosis may also require more than 2 years of chemotherapy and second-line therapies with narrow therapeutic index . In a clinical study involving patients with pulmonary multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis, treatment of delamanid in combination with WHO-recommended optimised background treatment regimen was associated with improved treatment outcomes and reduced mortality rate . Spontaneous resistance to delamanid was observed during treatment, where mutation in one of the 5 F420 coenzymes responsible for bioactivation of delamanid contributes to this effect . Delamanid is approved by the EMA and is marketed under the trade name Deltyba as oral tablets. It is marketed by Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan).

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) .

Delamanid
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Delamanid
Generic	Delamanid
Delamanid Other Names	Delamanid
Type
Formula	C₂₅H₂₅F₃N₄O₆
Weight	Average: 534.492 Monoisotopic: 534.17261903
Protein binding	Delamanid highly binds to all plasma proteins with a binding to total proteins of ≥99.5% .
Groups	Approved, Investigational
Therapeutic Class
Manufacturer
Available Country
Last Updated:	September 19, 2023 at 7:00 am

Uses

Delamanid is an antibiotic used to treat multidrug resistant tuberculosis.

Indicated for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability .

Delamanid is also used to associated treatment for these conditions: Pulmonary Multi-Drug Resistant Tuberculosis (MDR-TB)

How Delamanid works

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 .

Toxicity

While there have been no cases of delamanid overdose, some adverse reactions were observed at a higher frequency and the rate of QT prolongation increased in a dose-related manner. Treatment of overdose should involve immediate measures to remove delamanid from the gastrointestinal tract and supportive care as required. Frequent ECG monitoring should be performed .

Studies of genotoxicity and carcinogenic potential reveal no significant effects on humans. Delamanid and/or its metabolites have the potential to affect cardiac repolarisation via blockade of hERG potassium channels. During repeat-dose studies in dogs, foamy macrophages were observed in lymphoid tissue of various organs with delamanid treatment although clinical relevance of this finding was not established. Repeat-dose toxicity studies in rabbits revealed an inhibitory effect of delamanid and/or its metabolites on clotting factors II, VII, IX, and X via inhibition of vitamin K production . Embryo-fetal toxicity was observed at maternally toxic dosages in reproductive studies involving rabbits .

Food Interaction

Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of delamanid.
Take with food. Taking delamanid with food increases its bioavailability.

Volume of Distribution

The apparent volume of distribution (Vz/F) is 2,100 L. Pharmacokinetic data in animals have shown excretion of delamanid and/or its metabolites into breast milk. In lactating rats, the Cmax for delamanid in breast milk was 4-fold higher than that of the blood .

Elimination Route

Following a single oral dose administration of 100 mg delamanid, the peak plasma concentration was 135 ng/mL . Steady-state concentration is reached after 10-14 days . Delamanid plasma exposure increases less than proportionally with increasing dose. In animal models (dog, rat, mouse), the oral bioavailability of delamanid was reported to be 35%–60% . The absolute oral bioavailability in humans is estimated to range from 25 to 47% . Oral bioavailability in humans is enhanced when administered with a standard meal, by about 2.7 fold compared to fasting conditions because delamanid exhibits poor water solubility .