Peringatan Keamanan

To this date, there is no documented experience with the treatment of a pretomanid overdose. The FDA label advises that general supportive measures are taken to manage an overdose, such as monitoring vital signs in addition to performing ECG testing for a prolonged QT interval in the case of an overdose.L8048

Pretomanid

DB05154

small molecule approved

Deskripsi

Persistent forms of tuberculosis (TB) have proven to be a major cause of global morbidity and mortality and a cause for significant concern. Research in recent years has been geared toward the development of novel therapies that target persistent forms of this disease, which have shown resistance to standard therapy regimens.A182915 Pretomanid is an antimycobacterial agent that is administered with Bedaquiline and Linezolid to treat resistant forms of pulmonary TB. It was the first TB drug developed by a nonprofit organization, known as TB Alliance, and was granted FDA approval on August 14, 2019.L8048,L8066 Unlike other therapeutic regimens for the treatment of resistant TB, which may take 18 months or longer and may not be effective, the pretomanid-containing regimen allows for a more efficacious and shorter duration of treatment with fewer drugs.L8066

Struktur Molekul 2D

Berat 359.2574
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) The elimination half-life was determined to be 16.9-17.4 hours in a pharmacokinetic study of healthy subjects.[L8048] An FDA briefing document reports a half-life of 18 hours.[L8057]
Volume Distribusi A pharmacokinetic modeling study estimated the volume of distribution at 130 ± 5L.[A182888] A pharmacokinetic study in healthy volunteers determined a volume of distribution of about 180 ± 51.3L in fasted state and 97.0 ± 17.2L in the fed state.[L8048]
Klirens (Clearance) The clearance of pretomanid in a pharmacokinetic simulation study has been estimated at 4.8 ± 0.2 liters/h.[A182888] According to the FDA label, the clearance of a single 200 mg oral dose of pretomanid is estimated to be 7.6 liters/h in the fasted state, and 3.9 liters/h in the fed state.[L8048]

Absorpsi

This drug is absorbed in the gastrointestinal tract. The steady-state Cmax of pretomanid was estimated to be 1.7 ?g/mL after a single 200mg oral dose.L8048 In a separate pharmacokinetic modeling study, the Cmax of a 200mg dose was 1.1 ?g/ml.A182888 Tmax in a study of healthy subjects in the fed or unfed state was achieved within 4 to 5 hours.L8048 The AUC in the same study was found to be about 28.1 ?g•hr/mL in the fasted state and about 51.6 ?g•hr/mL in the fed state, showing higher absorption when taken with high-calorie and high-fat food.L8048

Metabolisme

Various reductive and oxidative pathways are responsible for pretomanid metabolism, with no single major metabolic pathway identified. According to in vitro studies, CYP3A4 is responsible for a 20% contribution to the metabolism of pretomanid.L8048

Rute Eliminasi

Healthy adult male volunteers were administered a 1,100 mg oral dose of radiolabeled pretomanid in one pharmacokinetic study. An average of about 53% of the radioactive dose was found to be excreted in the urine. Approximately 38% was measured mainly as metabolites in the feces. A estimated 1% of the radiolabeled dose was measured as unchanged drug in the urine.L8048

Interaksi Makanan

2 Data
  • 1. Avoid alcohol. Consuming alcohol may increase the risk of hepatotoxicity.
  • 2. Take with food.

Interaksi Obat

672 Data
Phenytoin The serum concentration of Pretomanid can be decreased when it is combined with Phenytoin.
Fosphenytoin The serum concentration of Pretomanid can be decreased when it is combined with Fosphenytoin.
Bexarotene The serum concentration of Pretomanid can be decreased when it is combined with Bexarotene.
Bosentan The serum concentration of Pretomanid can be decreased when it is combined with Bosentan.
Nafcillin The serum concentration of Pretomanid can be decreased when it is combined with Nafcillin.
Modafinil The serum concentration of Pretomanid can be decreased when it is combined with Modafinil.
Etravirine The serum concentration of Pretomanid can be decreased when it is combined with Etravirine.
Avasimibe The serum concentration of Pretomanid can be decreased when it is combined with Avasimibe.
Echinacea The serum concentration of Pretomanid can be decreased when it is combined with Echinacea.
Dexamethasone acetate The serum concentration of Pretomanid can be decreased when it is combined with Dexamethasone acetate.
Pitolisant The serum concentration of Pretomanid can be decreased when it is combined with Pitolisant.
Metreleptin The metabolism of Pretomanid can be increased when combined with Metreleptin.
Topiramate The metabolism of Pretomanid can be increased when combined with Topiramate.
Rifabutin The metabolism of Pretomanid can be increased when combined with Rifabutin.
Felbamate The metabolism of Pretomanid can be increased when combined with Felbamate.
Genistein The metabolism of Pretomanid can be increased when combined with Genistein.
Oritavancin The metabolism of Pretomanid can be increased when combined with Oritavancin.
Rufinamide The metabolism of Pretomanid can be increased when combined with Rufinamide.
Armodafinil The metabolism of Pretomanid can be increased when combined with Armodafinil.
Glycerol phenylbutyrate The metabolism of Pretomanid can be increased when combined with Glycerol phenylbutyrate.
Eslicarbazepine acetate The metabolism of Pretomanid can be increased when combined with Eslicarbazepine acetate.
Lesinurad The metabolism of Pretomanid can be increased when combined with Lesinurad.
Asunaprevir The metabolism of Pretomanid can be increased when combined with Asunaprevir.
Sarilumab The metabolism of Pretomanid can be increased when combined with Sarilumab.
Esketamine The metabolism of Pretomanid can be increased when combined with Esketamine.
Calcitriol The metabolism of Pretomanid can be increased when combined with Calcitriol.
Vitamin E The metabolism of Pretomanid can be increased when combined with Vitamin E.
Flunisolide The metabolism of Pretomanid can be increased when combined with Flunisolide.
Troglitazone The metabolism of Pretomanid can be increased when combined with Troglitazone.
Butalbital The metabolism of Pretomanid can be increased when combined with Butalbital.
Flucloxacillin The metabolism of Pretomanid can be increased when combined with Flucloxacillin.
Acetaminophen The metabolism of Pretomanid can be increased when combined with Acetaminophen.
Clobazam The serum concentration of Clobazam can be increased when it is combined with Pretomanid.
Aminoglutethimide The metabolism of Pretomanid can be increased when combined with Aminoglutethimide.
Beclomethasone dipropionate The metabolism of Pretomanid can be increased when combined with Beclomethasone dipropionate.
Griseofulvin The metabolism of Pretomanid can be increased when combined with Griseofulvin.
Secobarbital The metabolism of Pretomanid can be increased when combined with Secobarbital.
Cerivastatin The serum concentration of Cerivastatin can be increased when it is combined with Pretomanid.
Betamethasone The metabolism of Pretomanid can be increased when combined with Betamethasone.
Quinine The serum concentration of Quinine can be increased when it is combined with Pretomanid.
Chlorpromazine The metabolism of Pretomanid can be increased when combined with Chlorpromazine.
Dicloxacillin The metabolism of Pretomanid can be increased when combined with Dicloxacillin.
Rofecoxib The metabolism of Pretomanid can be increased when combined with Rofecoxib.
Fluocinolone acetonide The metabolism of Pretomanid can be increased when combined with Fluocinolone acetonide.
Medroxyprogesterone acetate The metabolism of Pretomanid can be increased when combined with Medroxyprogesterone acetate.
Triamcinolone The metabolism of Pretomanid can be increased when combined with Triamcinolone.
Testosterone The serum concentration of Testosterone can be increased when it is combined with Pretomanid.
Clofibrate The metabolism of Pretomanid can be increased when combined with Clofibrate.
Hydrocortisone The serum concentration of Hydrocortisone can be increased when it is combined with Pretomanid.
Mometasone The metabolism of Pretomanid can be increased when combined with Mometasone.
Hydrocortamate The metabolism of Pretomanid can be increased when combined with Hydrocortamate.
Oxcarbazepine The metabolism of Pretomanid can be increased when combined with Oxcarbazepine.
Phenylbutazone The metabolism of Pretomanid can be increased when combined with Phenylbutazone.
Mifepristone The metabolism of Pretomanid can be increased when combined with Mifepristone.
Methylphenobarbital The metabolism of Pretomanid can be increased when combined with Methylphenobarbital.
Terbinafine The metabolism of Pretomanid can be increased when combined with Terbinafine.
Prednisolone The metabolism of Pretomanid can be increased when combined with Prednisolone.
Ethanol The metabolism of Pretomanid can be increased when combined with Ethanol.
Norgestimate The metabolism of Pretomanid can be increased when combined with Norgestimate.
Methylprednisolone The metabolism of Pretomanid can be increased when combined with Methylprednisolone.
Metyrapone The metabolism of Pretomanid can be increased when combined with Metyrapone.
Clobetasol propionate The metabolism of Pretomanid can be increased when combined with Clobetasol propionate.
Probenecid The metabolism of Pretomanid can be increased when combined with Probenecid.
Fluocinonide The metabolism of Pretomanid can be increased when combined with Fluocinonide.
Sulfinpyrazone The metabolism of Pretomanid can be increased when combined with Sulfinpyrazone.
Thiamylal The metabolism of Pretomanid can be increased when combined with Thiamylal.
Rifapentine The serum concentration of Pretomanid can be decreased when it is combined with Rifapentine.
Budesonide The metabolism of Pretomanid can be increased when combined with Budesonide.
Corticotropin The metabolism of Pretomanid can be increased when combined with Corticotropin.
Cefradine The metabolism of Pretomanid can be increased when combined with Cefradine.
Amobarbital The metabolism of Pretomanid can be increased when combined with Amobarbital.
Aprobarbital The metabolism of Pretomanid can be increased when combined with Aprobarbital.
Cortisone acetate The metabolism of Pretomanid can be increased when combined with Cortisone acetate.
Paramethasone The metabolism of Pretomanid can be increased when combined with Paramethasone.
Barbital The metabolism of Pretomanid can be increased when combined with Barbital.
Deferasirox The metabolism of Pretomanid can be increased when combined with Deferasirox.
Tesmilifene The metabolism of Pretomanid can be increased when combined with Tesmilifene.
Clevidipine The metabolism of Pretomanid can be increased when combined with Clevidipine.
Fosaprepitant The metabolism of Pretomanid can be increased when combined with Fosaprepitant.
Seratrodast The metabolism of Pretomanid can be increased when combined with Seratrodast.
Perampanel The metabolism of Pretomanid can be increased when combined with Perampanel.
Formestane The metabolism of Pretomanid can be increased when combined with Formestane.
Fluprednidene The metabolism of Pretomanid can be increased when combined with Fluprednidene.
Fluocortolone The metabolism of Pretomanid can be increased when combined with Fluocortolone.
Barbexaclone The metabolism of Pretomanid can be increased when combined with Barbexaclone.
Difluocortolone The metabolism of Pretomanid can be increased when combined with Difluocortolone.
Meprednisone The metabolism of Pretomanid can be increased when combined with Meprednisone.
Dexamethasone isonicotinate The metabolism of Pretomanid can be increased when combined with Dexamethasone isonicotinate.
Deflazacort The metabolism of Pretomanid can be increased when combined with Deflazacort.
Cortivazol The metabolism of Pretomanid can be increased when combined with Cortivazol.
Prednylidene The metabolism of Pretomanid can be increased when combined with Prednylidene.
Cloprednol The metabolism of Pretomanid can be increased when combined with Cloprednol.
Fluticasone The metabolism of Pretomanid can be increased when combined with Fluticasone.
Estradiol acetate The metabolism of Pretomanid can be increased when combined with Estradiol acetate.
Estradiol benzoate The metabolism of Pretomanid can be increased when combined with Estradiol benzoate.
Estradiol cypionate The metabolism of Pretomanid can be increased when combined with Estradiol cypionate.
Estradiol dienanthate The metabolism of Pretomanid can be increased when combined with Estradiol dienanthate.
Estradiol valerate The metabolism of Pretomanid can be increased when combined with Estradiol valerate.
Mometasone furoate The metabolism of Pretomanid can be increased when combined with Mometasone furoate.
Hydrocortisone acetate The metabolism of Pretomanid can be increased when combined with Hydrocortisone acetate.

Target Protein

Cyclopropane mycolic acid synthase 1 cmaA1
Cyclopropane mycolic acid synthase 2 cmaA2
Cyclopropane mycolic acid synthase 3 pcaA
Probable fatty acid synthase Fas (Fatty acid synthetase) fas
Uncharacterized MFS-type transporter EfpA efpA
Nucleoid-associated protein Lsr2 lsr2
Cyd operon, Mycobacterium tuberculosis cydC
Enoyl-[acyl-carrier-protein] reductase [NADH] inhA

Referensi & Sumber

Synthesis reference: Thompson AM, Bonnet M, Lee HH, et al. Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid. ACS Med Chem Lett. 2017;8(12):1275–1280. Published 2017 Nov 13. doi:10.1021/acsmedchemlett.7b00356
Artikel (PubMed)
  • PMID: 30833432
    Xu J, Li SY, Almeida DV, Tasneen R, Barnes-Boyle K, Converse PJ, Upton AM, Mdluli K, Fotouhi N, Nuermberger EL: Contribution of Pretomanid to Novel Regimens Containing Bedaquiline with either Linezolid or Moxifloxacin and Pyrazinamide in Murine Models of Tuberculosis. Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: AAC.00021-19. doi: 10.1128/AAC.00021-19. Print 2019 May.
  • PMID: 29661865
    Lyons MA: Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients. Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: AAC.02359-17. doi: 10.1128/AAC.02359-17. Print 2018 Jul.
  • PMID: 29572459
    Baptista R, Fazakerley DM, Beckmann M, Baillie L, Mur LAJ: Untargeted metabolomics reveals a new mode of action of pretomanid (PA-824). Sci Rep. 2018 Mar 23;8(1):5084. doi: 10.1038/s41598-018-23110-1.
  • PMID: 29259747
    Thompson AM, Bonnet M, Lee HH, Franzblau SG, Wan B, Wong GS, Cooper CB, Denny WA: Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid. ACS Med Chem Lett. 2017 Nov 13;8(12):1275-1280. doi: 10.1021/acsmedchemlett.7b00356. eCollection 2017 Dec 14.
  • PMID: 19641733
    Manjunatha U, Boshoff HI, Barry CE: The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926.
  • PMID: 18079742
    Sacchettini JC, Rubin EJ, Freundlich JS: Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. Nat Rev Microbiol. 2008 Jan;6(1):41-52. doi: 10.1038/nrmicro1816.
  • PMID: 29187395
    Cano-Muniz S, Anthony R, Niemann S, Alffenaar JC: New Approaches and Therapeutic Options for Mycobacterium tuberculosis in a Dormant State. Clin Microbiol Rev. 2017 Nov 29;31(1). pii: 31/1/e00060-17. doi: 10.1128/CMR.00060-17. Print 2018 Jan.
  • PMID: 28584788
    Kwon YS: Clinical Implications of New Drugs and Regimens for the Treatment of Drug-resistant Tuberculosis. Chonnam Med J. 2017 May;53(2):103-109. doi: 10.4068/cmj.2017.53.2.103. Epub 2017 May 25.
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Contoh Produk & Brand

Produk: 6 • International brands: 0
Produk
  • Pretomanid
    Tablet • 200 mg/1 • Oral • US • Approved
  • Pretomanid Fgk
    Tablet • 200 mg • Oral • EU • Approved
  • Pretomanid Fgk
    Tablet • 200 mg • Oral • EU • Approved
  • Pretomanid Fgk
    Tablet • 200 mg • Oral • EU • Approved
  • Pretomanid Fgk
    Tablet • 200 mg • Oral • EU • Approved
  • Pretomanid Fgk
    Tablet • 200 mg • Oral • EU • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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