Identification

Name
Delamanid
Accession Number
DB11637
Type
Small Molecule
Groups
Approved, Investigational
Description

Delamanid is an anti-tuberculosis agent derived from the nitro-dihydro-imidazooxazole class of compounds that inhibits mycolic acid synthesis of bacterial cell wall [1]. 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 [4]. 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 [1]. 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 [6]. 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).

Structure
Thumb
Synonyms
Not Available
External IDs
OPC 67683 / OPC-67683
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DeltybaTablet, film coated50 mgOralOtsuka Novel Products Gmb H2014-04-28Not applicableEu
DeltybaTablet, film coated50 mgOralOtsuka Novel Products Gmb H2014-04-28Not applicableEu
DeltybaTablet, film coated50 mgOralOtsuka Novel Products Gmb H2014-04-28Not applicableEu
DeltybaTablet, film coated50 mgOralOtsuka Novel Products Gmb H2014-04-28Not applicableEu
Categories
UNII
8OOT6M1PC7
CAS number
681492-22-8
Weight
Average: 534.492
Monoisotopic: 534.17261903
Chemical Formula
C25H25F3N4O6
InChI Key
XDAOLTSRNUSPPH-XMMPIXPASA-N
InChI
InChI=1S/C25H25F3N4O6/c1-24(15-31-14-22(32(33)34)29-23(31)38-24)16-35-18-4-2-17(3-5-18)30-12-10-20(11-13-30)36-19-6-8-21(9-7-19)37-25(26,27)28/h2-9,14,20H,10-13,15-16H2,1H3/t24-/m1/s1
IUPAC Name
1-(4-{[(2R)-2-methyl-6-nitro-2H,3H-imidazo[2,1-b][1,3]oxazol-2-yl]methoxy}phenyl)-4-[4-(trifluoromethoxy)phenoxy]piperidine
SMILES
C[C@]1(COC2=CC=C(C=C2)N2CCC(CC2)OC2=CC=C(OC(F)(F)F)C=C2)CN2C=C(N=C2O1)[N+]([O-])=O

Pharmacology

Indication

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 [6].

Associated Conditions
Pharmacodynamics

The minimum inhibitory concentrations (MIC) of delamanid against Mycobacterium tuberculosis isolates ranges from 0.006 to 0.024 g/mL [2]. Among non-tuberculosis mycobacteria, delamanid has in vitro activity against M. kansasii and M. bovis [2]. Delamanid has no in vitro activity against Gram negative or positive bacterial species and does not display cross-resistance to other anti-tuberculosis drugs [6]. In murine models of chronic tuberculosis, the reduction of M. tuberculosis colony counts by delamanid was demonstrated in a dose-dependent manner [2]. 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 [6, 2]. Animal studies indicate that delamanid may attenuate vitamin K-dependent blood clotting, increase prothrombin time (PT), and activated partial thromboplastin time (APTT) [2].

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 [2] against both growing and nongrowing mycobacteria [3]. Mutations in one of five coenzyme F420 genes, fgd, Rv3547, fbiA, fbiB, and fbiC has been proposed as the mechanism of resistance to delamanid [2]. Upon activation, the radical intermediate formed between delamanid and desnitro-imidazooxazole derivative [5] 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 [6]. Nitroimidazooxazole derivative is thought to generate reactive nitrogen species, including nitrogen oxide (NO). However unlike isoniazid, delamanid does not alpha-mycolic acid [2].

Absorption

Following a single oral dose administration of 100 mg delamanid, the peak plasma concentration was 135 ng/mL [4]. Steady-state concentration is reached after 10-14 days [5]. 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% [2]. The absolute oral bioavailability in humans is estimated to range from 25 to 47% [3]. Oral bioavailability in humans is enhanced when administered with a standard meal, by about 2.7 fold compared to fasting conditions [6] because delamanid exhibits poor water solubility [3].

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 [6].

Protein binding

Delamanid highly binds to all plasma proteins with a binding to total proteins of ≥99.5% [6].

Metabolism

Delamanid predominantly undergoes metabolism by albumin and to a lesser extent, CYP3A4. [6]. The metabolism of delamanid may also be mediated by hepatic CYP1A1, CYP2D6, and CYP2E1 to a lesser extent [31966]. 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 [4]. While they do not retain significant pharmacological activity, they may still contribute to QT prolongation [3]. This is especially true for the main metabolite of delamanid, M1 (DM-6705) [2, 3].

Delamanid is predominantly metabolized by serum albumin to form M1 (DM-6705) via hydrolytic cleavage of the 6-nitro-2,3-dihydroimidazo[2,1-b] oxazole moiety. The formation of this major metabolite is suggested to be a crucial starting point in the metabolic pathway of delamanid [4]. 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) [4]. 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) [4]. The third pathway involves the hydrolytic cleavage of the oxazole ring to form M5 (DM-6706) [4].

Route of elimination

Delamanid is excreted primarily in the stool, with less than 5% excretion in the urine [3].

Half life

The half life ranges from 30 to 38 hours [6].

Clearance
Not Available
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 [6].

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 [6, 2]. Embryo-fetal toxicity was observed at maternally toxic dosages in reproductive studies involving rabbits [6].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Delamanid can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Delamanid.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Delamanid.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Delamanid.
5-androstenedioneThe metabolism of Delamanid can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Delamanid can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Delamanid.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Delamanid.
AbexinostatThe risk or severity of QTc prolongation can be increased when Delamanid is combined with Abexinostat.
AbirateroneThe metabolism of Delamanid can be decreased when combined with Abiraterone.
Food Interactions
Not Available

References

General References
  1. Skripconoka V, Danilovits M, Pehme L, Tomson T, Skenders G, Kummik T, Cirule A, Leimane V, Kurve A, Levina K, Geiter LJ, Manissero D, Wells CD: Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J. 2013 Jun;41(6):1393-400. doi: 10.1183/09031936.00125812. Epub 2012 Sep 27. [PubMed:23018916]
  2. Lewis JM, Sloan DJ: The role of delamanid in the treatment of drug-resistant tuberculosis. Ther Clin Risk Manag. 2015 May 13;11:779-91. doi: 10.2147/TCRM.S71076. eCollection 2015. [PubMed:25999726]
  3. Szumowski JD, Lynch JB: Profile of delamanid for the treatment of multidrug-resistant tuberculosis. Drug Des Devel Ther. 2015 Jan 29;9:677-82. doi: 10.2147/DDDT.S60923. eCollection 2015. [PubMed:25678771]
  4. Sasahara K, Shimokawa Y, Hirao Y, Koyama N, Kitano K, Shibata M, Umehara K: Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo. Drug Metab Dispos. 2015 Aug;43(8):1267-76. doi: 10.1124/dmd.115.064527. Epub 2015 Jun 8. [PubMed:26055620]
  5. Xavier AS, Lakshmanan M: Delamanid: A new armor in combating drug-resistant tuberculosis. J Pharmacol Pharmacother. 2014 Jul;5(3):222-4. doi: 10.4103/0976-500X.136121. [PubMed:25210407]
  6. Deltyba, INN-Delamanid - European Medicines Agency - Europa EU [Link]
External Links
ChemSpider
4981055
ChEBI
134742
ChEMBL
CHEMBL218650
Wikipedia
Delamanid
ATC Codes
J04AK06 — Delamanid
MSDS
Download (218 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentPediatric / Tuberculosis, Multidrug Resistant1
1, 2RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis Infection1
2Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis Infection1
2Active Not RecruitingTreatmentPediatric / Tuberculosis, Multidrug Resistant1
2CompletedTreatmentExtensively Drug Resistant Tuberculosis / Pulmonary Tuberculosis (TB) / Tuberculosis, Multidrug Resistant1
2CompletedTreatmentPulmonary Tuberculosis (TB)1
2CompletedTreatmentTuberculosis Infection1
2CompletedTreatmentTuberculosis, Multidrug Resistant1
2RecruitingTreatmentTuberculosis, Multidrug Resistant1
3CompletedTreatmentTuberculosis, Multidrug Resistant1
3Not Yet RecruitingPreventionMulti-Drug Resistant Tuberculosis1
3RecruitingTreatmentTuberculosis, Multidrug Resistant1
3WithdrawnTreatmentTuberculosis Multi Drug Resistant Active1
4RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
Not AvailableRecruitingNot AvailableTuberculosis Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral50 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00222 mg/mLALOGPS
logP5.71ALOGPS
logP6.14ChemAxon
logS-5.4ALOGPS
pKa (Strongest Basic)5.51ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area101.12 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity124.85 m3·mol-1ChemAxon
Polarizability51.59 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Phenylpiperidines
Direct Parent
Phenylpiperidines
Alternative Parents
Aminophenyl ethers / Aniline and substituted anilines / Dialkylarylamines / Nitroaromatic compounds / Nitroimidazoles / Phenoxy compounds / Alkyl aryl ethers / N-substituted imidazoles / Imidolactams / Heteroaromatic compounds
show 10 more
Substituents
Phenylpiperidine / Aminophenyl ether / Phenoxy compound / Nitroaromatic compound / Nitroimidazole / Phenol ether / Tertiary aliphatic/aromatic amine / Dialkylarylamine / Aniline or substituted anilines / Alkyl aryl ether
show 32 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Enzymes

Kind
Protein
Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Pharmacological action
Yes
Actions
Substrate
General Function
Involved in a F420-dependent anti-oxidant mechanism that protects M.tuberculosis against oxidative stress and bactericidal agents. Catalyzes the F420H(2)-dependent two-electron reduction of quinones to dihydroquinones, thereby preventing the formation of cytotoxic semiquinones obtained by the one-electron reduction pathway (PubMed:23240649). In vitro, catalyzes the reduction of both benzoquinone and naphthoquinone analogs; since menaquinone is the sole quinone electron carrier in the respiratory chain in M.tuberculosis, the physiological electron acceptor for Fqr-mediated F420H(2) oxidation is therefore likely to be the endogenous menaquinone found in the membrane fraction of M.tuberculosis (PubMed:23240649). Is able to use F420 species with two and five glutamate residues in its polyglutamate tail (PubMed:22023140). Cannot use NADH or NADPH instead of F420H(2) as the electron donor (PubMed:23240649).
Specific Function
Coenzyme f420 binding
Gene Name
ddn
Uniprot ID
P9WP15
Uniprot Name
Deazaflavin-dependent nitroreductase
Molecular Weight
17370.87 Da
References
  1. Lewis JM, Sloan DJ: The role of delamanid in the treatment of drug-resistant tuberculosis. Ther Clin Risk Manag. 2015 May 13;11:779-91. doi: 10.2147/TCRM.S71076. eCollection 2015. [PubMed:25999726]
  2. Szumowski JD, Lynch JB: Profile of delamanid for the treatment of multidrug-resistant tuberculosis. Drug Des Devel Ther. 2015 Jan 29;9:677-82. doi: 10.2147/DDDT.S60923. eCollection 2015. [PubMed:25678771]
  3. Xavier AS, Lakshmanan M: Delamanid: A new armor in combating drug-resistant tuberculosis. J Pharmacol Pharmacother. 2014 Jul;5(3):222-4. doi: 10.4103/0976-500X.136121. [PubMed:25210407]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Deltyba, INN-Delamanid - European Medicines Agency - Europa EU [Link]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Deltyba, INN-Delamanid - European Medicines Agency - Europa EU [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Deltyba, INN-Delamanid - European Medicines Agency - Europa EU [Link]

Drug created on October 17, 2016 15:29 / Updated on November 02, 2018 07:13