Delamanid API Manufacturers

General Description:

Delamanid, identified by CAS number 681492-22-8, is a notable compound with significant therapeutic applications. 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 and . 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).

Indications:

This drug is primarily indicated for: 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 . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Delamanid undergoes metabolic processing primarily in: Delamanid predominantly undergoes metabolism by albumin and to a lesser extent, CYP3A4. . The metabolism of delamanid may also be mediated by hepatic CYP1A1, CYP2D6, and CYP2E1 to a lesser extent . Four major metabolites (M1–M4) have been identified in plasma in patients receiving delamanid where M1 and M3 accounts for 13%–18% of the total plasma exposure in humans . While they do not retain significant pharmacological activity, they may still contribute to QT prolongation . This is especially true for the main metabolite of delamanid, M1 (DM-6705) . Delamanid is predominantly metabolized by serum albumin to form M1 (DM-6705) via hydrolytic cleavage of the 6-nitro-2,3-dihydroimidazo oxazole moiety. The formation of this major metabolite is suggested to be a crucial starting point in the metabolic pathway of delamanid . M1 (DM-6705) can be further catalyzed by three pathways. In the first metabolic pathway, DM-6705 undergoes hydroxylation of the oxazole moiety to form M2 ((4RS,5S)-DM-6720), followed by CYP3A4-mediated oxidation of hydroxyl group and tautomerization of oxazole to an imino-ketone metabolite, M3 ((S)-DM-6718) . The second metabolic pathway involves the hydrolysis and deamination of the oxazole amine to form M4 (DM-6704) followed by hydroxylation to M6 ((4R,5S)-DM-6721) and M7 ((4S,5S)-DM-6722) and oxidation of oxazole to another ketone metabolite, M8 ((S)-DM-6717) . The third pathway involves the hydrolytic cleavage of the oxazole ring to form M5 (DM-6706) . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Delamanid are crucial for its therapeutic efficacy: 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 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Delamanid is an important consideration for its dosing schedule: The half life ranges from 30 to 38 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Delamanid exhibits a strong affinity for binding with plasma proteins: Delamanid highly binds to all plasma proteins with a binding to total proteins of ≥99.5% . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Delamanid from the body primarily occurs through: Delamanid is excreted primarily in the stool, with less than 5% excretion in the urine . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Delamanid is distributed throughout the body with a volume of distribution of: 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 . This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Delamanid exerts its therapeutic effects through: 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) . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Delamanid functions by: 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Delamanid belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group, classified under the direct parent group Phenylpiperidines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Piperidines class, specifically within the Phenylpiperidines subclass.

Categories:

Delamanid is categorized under the following therapeutic classes: Antiinfectives for Systemic Use, Antimycobacterials, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Drugs for Treatment of Tuberculosis, Imidazoles, Moderate Risk QTc-Prolonging Agents, Nitro Compounds, QTc Prolonging Agents. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.