Peringatan Keamanan

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 L1407.

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 L1407, A31966. Embryo-fetal toxicity was observed at maternally toxic dosages in reproductive studies involving rabbits L1407.

Delamanid

DB11637

small molecule approved investigational

Deskripsi

Delamanid is an anti-tuberculosis agent derived from the nitro-dihydro-imidazooxazole class of compounds that inhibits mycolic acid synthesis of bacterial cell wall A31965. 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 DB00951 and DB01045. Multidrug-resistant tuberculosis may also require more than 2 years of chemotherapy and second-line therapies with narrow therapeutic index A31968. 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 A31965. 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 L1407. 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).

Struktur Molekul 2D

Berat 534.492
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The half life ranges from 30 to 38 hours [L1407].
Volume Distribusi 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 [L1407].
Klirens (Clearance) -

Absorpsi

Following a single oral dose administration of 100 mg delamanid, the peak plasma concentration was 135 ng/mL A31968. Steady-state concentration is reached after 10-14 days A31978. 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% A31966. The absolute oral bioavailability in humans is estimated to range from 25 to 47% A31967. Oral bioavailability in humans is enhanced when administered with a standard meal, by about 2.7 fold compared to fasting conditions L1407 because delamanid exhibits poor water solubility A31967.

Metabolisme

Delamanid predominantly undergoes metabolism by albumin and to a lesser extent, CYP3A4. L1407. 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 A31968. While they do not retain significant pharmacological activity, they may still contribute to QT prolongation A31967. This is especially true for the main metabolite of delamanid, M1 (DM-6705) A31966, A31967. Delamanid is predominantly metabolized by serum albumin to form M1 (DM-6705) via hydrolytic cleavage of the 6-nitro-2,3-dihydroimidazo2,1-b oxazole moiety. The formation of this major metabolite is suggested to be a crucial starting point in the metabolic pathway of delamanid A31968. 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) A31968. 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) A31968. The third pathway involves the hydrolytic cleavage of the oxazole ring to form M5 (DM-6706) A31968.

Rute Eliminasi

Delamanid is excreted primarily in the stool, with less than 5% excretion in the urine A31967.

Interaksi Makanan

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

Interaksi Obat

449 Data
Berotralstat The risk or severity of QTc prolongation can be increased when Delamanid is combined with Berotralstat.
Levomenthol The risk or severity of QTc prolongation can be increased when Levomenthol is combined with Delamanid.
Fostemsavir The risk or severity of QTc prolongation can be increased when Fostemsavir is combined with Delamanid.
Relugolix The risk or severity of QTc prolongation can be increased when Relugolix is combined with Delamanid.
Leuprolide Leuprolide may increase the QTc-prolonging activities of Delamanid.
Goserelin Goserelin may increase the QTc-prolonging activities of Delamanid.
Octreotide Octreotide may increase the QTc-prolonging activities of Delamanid.
Oxytocin Oxytocin may increase the QTc-prolonging activities of Delamanid.
Esmolol Esmolol may increase the QTc-prolonging activities of Delamanid.
Bortezomib Bortezomib may increase the QTc-prolonging activities of Delamanid.
Betaxolol Betaxolol may increase the QTc-prolonging activities of Delamanid.
Fluconazole Fluconazole may increase the QTc-prolonging activities of Delamanid.
Erythromycin The serum concentration of Delamanid can be increased when it is combined with Erythromycin.
Dofetilide Dofetilide may increase the QTc-prolonging activities of Delamanid.
Azithromycin Azithromycin may increase the QTc-prolonging activities of Delamanid.
Citalopram The risk or severity of QTc prolongation can be increased when Delamanid is combined with Citalopram.
Moxifloxacin Moxifloxacin may increase the QTc-prolonging activities of Delamanid.
Nelfinavir Nelfinavir may increase the QTc-prolonging activities of Delamanid.
Pregabalin Pregabalin may increase the QTc-prolonging activities of Delamanid.
Ranolazine Ranolazine may increase the QTc-prolonging activities of Delamanid.
Benzatropine Benzatropine may increase the QTc-prolonging activities of Delamanid.
Anagrelide Anagrelide may increase the QTc-prolonging activities of Delamanid.
Sulfisoxazole Sulfisoxazole may increase the QTc-prolonging activities of Delamanid.
Isradipine Isradipine may increase the QTc-prolonging activities of Delamanid.
Disopyramide Disopyramide may increase the QTc-prolonging activities of Delamanid.
Clemastine Clemastine may increase the QTc-prolonging activities of Delamanid.
Atomoxetine Atomoxetine may increase the QTc-prolonging activities of Delamanid.
Ibutilide Ibutilide may increase the QTc-prolonging activities of Delamanid.
Valproic acid Valproic acid may increase the QTc-prolonging activities of Delamanid.
Amitriptyline Amitriptyline may increase the QTc-prolonging activities of Delamanid.
Methadone Methadone may increase the QTc-prolonging activities of Delamanid.
Olanzapine Olanzapine may increase the QTc-prolonging activities of Delamanid.
Cetirizine Cetirizine may increase the QTc-prolonging activities of Delamanid.
Terfenadine Terfenadine may increase the QTc-prolonging activities of Delamanid.
Diltiazem Diltiazem may increase the QTc-prolonging activities of Delamanid.
Protriptyline Protriptyline may increase the QTc-prolonging activities of Delamanid.
Alfuzosin Alfuzosin may increase the QTc-prolonging activities of Delamanid.
Trimethadione Trimethadione may increase the QTc-prolonging activities of Delamanid.
Buclizine Buclizine may increase the QTc-prolonging activities of Delamanid.
Mefloquine Mefloquine may increase the QTc-prolonging activities of Delamanid.
Clozapine The risk or severity of QTc prolongation can be increased when Delamanid is combined with Clozapine.
Grepafloxacin Grepafloxacin may increase the QTc-prolonging activities of Delamanid.
Doxylamine Doxylamine may increase the QTc-prolonging activities of Delamanid.
Mirtazapine Mirtazapine may increase the QTc-prolonging activities of Delamanid.
Timolol Timolol may increase the QTc-prolonging activities of Delamanid.
Treprostinil Treprostinil may increase the QTc-prolonging activities of Delamanid.
Digoxin Digoxin may increase the QTc-prolonging activities of Delamanid.
Sulpiride Sulpiride may increase the QTc-prolonging activities of Delamanid.
Nimodipine Nimodipine may increase the QTc-prolonging activities of Delamanid.
Sorafenib Sorafenib may increase the QTc-prolonging activities of Delamanid.
Dexbrompheniramine Dexbrompheniramine may increase the QTc-prolonging activities of Delamanid.
Promazine Promazine may increase the QTc-prolonging activities of Delamanid.
Hyoscyamine Hyoscyamine may increase the QTc-prolonging activities of Delamanid.
Triprolidine Triprolidine may increase the QTc-prolonging activities of Delamanid.
Prochlorperazine Prochlorperazine may increase the QTc-prolonging activities of Delamanid.
Cyproheptadine Cyproheptadine may increase the QTc-prolonging activities of Delamanid.
Droperidol Droperidol may increase the QTc-prolonging activities of Delamanid.
Imipramine Imipramine may increase the QTc-prolonging activities of Delamanid.
Enoxacin Enoxacin may increase the QTc-prolonging activities of Delamanid.
Quinine Quinine may increase the QTc-prolonging activities of Delamanid.
Chlorpromazine Chlorpromazine may increase the QTc-prolonging activities of Delamanid.
Pefloxacin Pefloxacin may increase the QTc-prolonging activities of Delamanid.
Sotalol Sotalol may increase the QTc-prolonging activities of Delamanid.
Oxaliplatin The risk or severity of QTc prolongation can be increased when Oxaliplatin is combined with Delamanid.
Foscarnet Foscarnet may increase the QTc-prolonging activities of Delamanid.
Erlotinib Erlotinib may increase the QTc-prolonging activities of Delamanid.
Ciprofloxacin Ciprofloxacin may increase the QTc-prolonging activities of Delamanid.
Toremifene Toremifene may increase the QTc-prolonging activities of Delamanid.
Nortriptyline Nortriptyline may increase the QTc-prolonging activities of Delamanid.
Amoxapine Amoxapine may increase the QTc-prolonging activities of Delamanid.
Fluorouracil Fluorouracil may increase the QTc-prolonging activities of Delamanid.
Lamotrigine Lamotrigine may increase the QTc-prolonging activities of Delamanid.
Perflutren Perflutren may increase the QTc-prolonging activities of Delamanid.
Cinnarizine Cinnarizine may increase the QTc-prolonging activities of Delamanid.
Propranolol Propranolol may increase the QTc-prolonging activities of Delamanid.
Atropine Atropine may increase the QTc-prolonging activities of Delamanid.
Voriconazole Voriconazole may increase the QTc-prolonging activities of Delamanid.
Ethosuximide Ethosuximide may increase the QTc-prolonging activities of Delamanid.
Cisapride Cisapride may increase the QTc-prolonging activities of Delamanid.
Chloroquine Chloroquine may increase the QTc-prolonging activities of Delamanid.
Amodiaquine Amodiaquine may increase the QTc-prolonging activities of Delamanid.
Imatinib Imatinib may increase the QTc-prolonging activities of Delamanid.
Nicardipine Nicardipine may increase the QTc-prolonging activities of Delamanid.
Efavirenz Efavirenz may increase the QTc-prolonging activities of Delamanid.
Astemizole Astemizole may increase the QTc-prolonging activities of Delamanid.
Adenosine Adenosine may increase the QTc-prolonging activities of Delamanid.
Galantamine Galantamine may increase the QTc-prolonging activities of Delamanid.
Tamoxifen Tamoxifen may increase the QTc-prolonging activities of Delamanid.
Thioridazine Thioridazine may increase the QTc-prolonging activities of Delamanid.
Moricizine Moricizine may increase the QTc-prolonging activities of Delamanid.
Trovafloxacin Trovafloxacin may increase the QTc-prolonging activities of Delamanid.
Moexipril Moexipril may increase the QTc-prolonging activities of Delamanid.
Tizanidine Tizanidine may increase the QTc-prolonging activities of Delamanid.
Ibandronate Ibandronate may increase the QTc-prolonging activities of Delamanid.
Apomorphine Apomorphine may increase the QTc-prolonging activities of Delamanid.
Azatadine Azatadine may increase the QTc-prolonging activities of Delamanid.
Trimipramine Trimipramine may increase the QTc-prolonging activities of Delamanid.
Risperidone Risperidone may increase the QTc-prolonging activities of Delamanid.
Pentamidine Pentamidine may increase the QTc-prolonging activities of Delamanid.
Gadobenic acid Gadobenic acid may increase the QTc-prolonging activities of Delamanid.

Referensi & Sumber

Artikel (PubMed)
  • PMID: 23018916
    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.
  • PMID: 25999726
    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.
  • PMID: 25678771
    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.
  • PMID: 26055620
    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.
  • PMID: 25210407
    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.

Contoh Produk & Brand

Produk: 5 • International brands: 0
Produk
  • Deltyba
    Tablet, film coated • 50 mg • Oral • EU • Approved
  • Deltyba
    Tablet, for suspension • 25 mg • Oral • EU • Approved
  • Deltyba
    Tablet, film coated • 50 mg • Oral • EU • Approved
  • Deltyba
    Tablet, film coated • 50 mg • Oral • EU • Approved
  • Deltyba
    Tablet, film coated • 50 mg • Oral • EU • Approved

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