Peringatan Keamanan

As an inhibitor of cortisol synthesis, overdose with osilodrostat may result in severe hypocortisolism.L12123 Symptoms may include nausea, vomiting, fatigue, hypotension, abdominal pain, loss of appetite, dizziness, and syncope. Treatment of overdose should include assessment of cortisol levels and supplementation with exogenous corticosteroids as necessary, as well as careful monitoring of the patient's heart rhythm, blood glucose, electrolytes, and blood pressure.L12123

Toxicity related to its osilodrostat's mechanism of action is difficult to observe in animal test subjects as human receptor profiles and densities for osilodrostat targets differ in humans as compared to these animals - for this reason, toxicological data gleaned from animal trials is of uncertain clinical relevance in humans.L12159

Osilodrostat

DB11837

small molecule approved investigational

Deskripsi

Osilodrostat is an inhibitor of 11?-hydroxylase (also referred to as CYP11B1), the enzyme that catalyzes the final step in the biosynthesis of endogenous cortisol.L12123 It is used to lower circulating cortisol levels in the treatment of Cushing's disease, a disorder in which cortisol levels are chronically and supraphysiologically elevated. Cushing's disease is often the result of ACTH hypersecretion secondary to a pituitary tumor, and surgical resection of the tumour is generally the treatment of choice.A191910 As an orally bioavailable drug therapy, osilodrostat provides a novel treatment option for patients in whom removal of the causative tumor is not an option or for whom previous pituitary surgery has not been curative.

Osilodrostat is manufactured by Novartis under the brand name Isturisa.L12123 It has undergone phase II clinical trials for the treatment of solid tumours, hypertension, and heart failure, but development for these indications was discontinued by Novartis in January 2013.A191850 Osilodrostat was approved for use in the EU in January 2020 for the treatment of endogenous Cushing's syndrome (i.e. Cushing's disease),A191850 and was granted FDA approval and Orphan Drug designation in the US in March 2020 for the same indication.L12162

Struktur Molekul 2D

Berat 227.242
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 of osilodrostat is approximately 4 hours.[L12123,A191850]
Volume Distribusi The median apparent volume of distribution of osilodrostat is 100 L.[L12123]
Klirens (Clearance) Data regarding the oral clearance of osilodrostat are not currently available.

Absorpsi

The oral absorption of osilodrostat is rapid, with a Tmax of approximately 1 hour,L12123 and assumed to be essentially complete.L12132 Exposure (i.e. AUC and Cmax) increases slightly more than dose-proportionately over the standard dosing range.L12132 Coadministration of osilodrostat with food does not affect its pharmacokinetics to a clinically significant extent.L12123 Age and gender do not affect pharmacokinetics, but bioavailability and total exposure is higher (though not clinically significant) in patients of Asian descent.L12123 Exposure to osilodrostat is greater in patients with moderate-severe hepatic impairment - prescribing information recommends a starting dose of 1mg twice daily in patients with moderate hepatic impairment (Child-Pugh B) and a starting dose of 1mg each evening in patients with severe hepatic impairment (Child-Pugh C).L12123

Metabolisme

Osilodrostat is extensively metabolized - approximately 80% of an orally administered dose is excreted as metabolites, and this is the predominant means of drug clearance.L12132 The most abundant metabolites in plasma are M35.4 (di-oxygenated osilodrostat), M16.5, and M24.9 at 51%, 9%, and 7% of the administered dose, respectively.L12132 The M34.5 and M24.9 metabolites have longer half-lives than the parent drug which may lead to accumulation with twice-daily dosing. Of the thirteen metabolites observed in the urine, the most abundant are M16.5 (osilodrostat glucuronide), M22 (a glucuronide conjugate of M34.5), and M24.9 at 17%, 13%, and 11% of the administered dose, respectively.L12132 The M34.5 metabolite accounts for less than 1% of the dose excreted in urine, but its glucuronide conjugate (M22) accounts for approximately 13%.L12132 The biotransformation of osilodrostat is mediated by multiple cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes, though no single enzyme appears to contribute >25% to the total clearance.L12123 Of the total clearance, approximately 26% is CYP-mediated, 19% is UGT-mediated, and 50% is mediated by other enzymes.L12132 The formation of M34.5, the major metabolite of osilodrostat, is likely non-CYP-mediated. The formation of osilodrostat glucuronide (M16.5), its major urinary metabolite, is catalyzed by UGT1A4, UGT2B7, and UGT2B10.L12132 In vitro data suggest that none of the metabolites contribute to the therapeutic efficacy of osilodrostat, but the M34.5 metabolite has been implicated in the inhibition and/or induction of multiple enzymes and transporters.L12123,L12132

Rute Eliminasi

Following oral administration of radiolabeled osilodrostat, 90.6% of the radioactivity was eliminated in the urine with only 1.58% in the feces.L12123 Only 5.2% of the administered dose was eliminated in the urine as unchanged parent drug, suggesting that metabolism followed by urinary elimination is osildrostat's primary means of clearance.L12123

Interaksi Makanan

1 Data
  • 1. Take with or without food. Administration with food slightly alters absorption, but not to a clinically significant extent.

Interaksi Obat

727 Data
Lomitapide The metabolism of Lomitapide can be decreased when combined with Osilodrostat.
Cilostazol The serum concentration of Cilostazol can be increased when it is combined with Osilodrostat.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Osilodrostat.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Osilodrostat.
Colchicine The metabolism of Colchicine can be decreased when combined with Osilodrostat.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Osilodrostat.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Osilodrostat.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Osilodrostat.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Osilodrostat.
Eszopiclone The metabolism of Eszopiclone can be decreased when combined with Osilodrostat.
Zopiclone The metabolism of Zopiclone can be decreased when combined with Osilodrostat.
Lovastatin The metabolism of Lovastatin can be decreased when combined with Osilodrostat.
Zolmitriptan The metabolism of Zolmitriptan can be decreased when combined with Osilodrostat.
Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Osilodrostat.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Osilodrostat.
Atomoxetine The metabolism of Atomoxetine can be decreased when combined with Osilodrostat.
(R)-warfarin The serum concentration of (R)-warfarin can be increased when it is combined with Osilodrostat.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Osilodrostat.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Osilodrostat.
(S)-Warfarin The serum concentration of (S)-Warfarin can be increased when it is combined with Osilodrostat.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Osilodrostat.
Agomelatine The serum concentration of Agomelatine can be increased when it is combined with Osilodrostat.
Pirfenidone The metabolism of Pirfenidone can be decreased when combined with Osilodrostat.
Tizanidine The serum concentration of Tizanidine can be increased when it is combined with Osilodrostat.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Osilodrostat.
Atorvastatin The metabolism of Atorvastatin can be decreased when combined with Osilodrostat.
Fluvoxamine The metabolism of Osilodrostat can be decreased when combined with Fluvoxamine.
Betaxolol The metabolism of Betaxolol can be decreased when combined with Osilodrostat.
Caffeine The metabolism of Caffeine can be decreased when combined with Osilodrostat.
Carmustine The metabolism of Carmustine can be decreased when combined with Osilodrostat.
Disopyramide The metabolism of Disopyramide can be decreased when combined with Osilodrostat.
Lidocaine The metabolism of Lidocaine can be decreased when combined with Osilodrostat.
Conjugated estrogens The metabolism of Conjugated estrogens can be decreased when combined with Osilodrostat.
Ropivacaine The metabolism of Ropivacaine can be decreased when combined with Osilodrostat.
Acetaminophen The metabolism of Acetaminophen can be decreased when combined with Osilodrostat.
Olanzapine The metabolism of Olanzapine can be decreased when combined with Osilodrostat.
Chlorzoxazone The metabolism of Chlorzoxazone can be decreased when combined with Osilodrostat.
Grepafloxacin The metabolism of Grepafloxacin can be decreased when combined with Osilodrostat.
Mirtazapine The metabolism of Mirtazapine can be decreased when combined with Osilodrostat.
Mexiletine The metabolism of Mexiletine can be decreased when combined with Osilodrostat.
Tacrine The metabolism of Tacrine can be decreased when combined with Osilodrostat.
Triamterene The metabolism of Triamterene can be decreased when combined with Osilodrostat.
Promazine The metabolism of Promazine can be decreased when combined with Osilodrostat.
Zolpidem The metabolism of Zolpidem can be decreased when combined with Osilodrostat.
Entecavir The metabolism of Entecavir can be decreased when combined with Osilodrostat.
Nabumetone The metabolism of Nabumetone can be decreased when combined with Osilodrostat.
Quinine The metabolism of Quinine can be decreased when combined with Osilodrostat.
Fluoxetine The metabolism of Fluoxetine can be decreased when combined with Osilodrostat.
Chlorpromazine The metabolism of Chlorpromazine can be decreased when combined with Osilodrostat.
Flutamide The metabolism of Flutamide can be decreased when combined with Osilodrostat.
Albendazole The metabolism of Albendazole can be decreased when combined with Osilodrostat.
Rofecoxib The metabolism of Rofecoxib can be decreased when combined with Osilodrostat.
Cinnarizine The metabolism of Cinnarizine can be decreased when combined with Osilodrostat.
Diclofenac The metabolism of Diclofenac can be decreased when combined with Osilodrostat.
Guanabenz The metabolism of Guanabenz can be decreased when combined with Osilodrostat.
Pemetrexed The metabolism of Pemetrexed can be decreased when combined with Osilodrostat.
Verapamil The metabolism of Osilodrostat can be decreased when combined with Verapamil.
Paroxetine The metabolism of Paroxetine can be decreased when combined with Osilodrostat.
Thiabendazole The metabolism of Thiabendazole can be decreased when combined with Osilodrostat.
Riluzole The metabolism of Riluzole can be decreased when combined with Osilodrostat.
Zileuton The metabolism of Zileuton can be decreased when combined with Osilodrostat.
Clopidogrel The metabolism of Clopidogrel can be decreased when combined with Osilodrostat.
Acyclovir The metabolism of Acyclovir can be decreased when combined with Osilodrostat.
Naproxen The metabolism of Naproxen can be decreased when combined with Osilodrostat.
Pentoxifylline The metabolism of Pentoxifylline can be decreased when combined with Osilodrostat.
Trifluoperazine The metabolism of Trifluoperazine can be decreased when combined with Osilodrostat.
Perphenazine The metabolism of Perphenazine can be decreased when combined with Osilodrostat.
Terbinafine The metabolism of Terbinafine can be decreased when combined with Osilodrostat.
Ranitidine The metabolism of Ranitidine can be decreased when combined with Osilodrostat.
Ethanol The metabolism of Ethanol can be decreased when combined with Osilodrostat.
Maprotiline The metabolism of Maprotiline can be decreased when combined with Osilodrostat.
Alosetron The metabolism of Alosetron can be decreased when combined with Osilodrostat.
Azelastine The metabolism of Azelastine can be decreased when combined with Osilodrostat.
Ethinylestradiol The metabolism of Ethinylestradiol can be decreased when combined with Osilodrostat.
Lomefloxacin The metabolism of Lomefloxacin can be decreased when combined with Osilodrostat.
Ramelteon The metabolism of Ramelteon can be decreased when combined with Osilodrostat.
Azathioprine The metabolism of Azathioprine can be decreased when combined with Osilodrostat.
Frovatriptan The metabolism of Frovatriptan can be decreased when combined with Osilodrostat.
Levobupivacaine The metabolism of Levobupivacaine can be decreased when combined with Osilodrostat.
Cinacalcet The metabolism of Cinacalcet can be decreased when combined with Osilodrostat.
Selegiline The metabolism of Selegiline can be decreased when combined with Osilodrostat.
Tocainide The metabolism of Tocainide can be decreased when combined with Osilodrostat.
Praziquantel The metabolism of Praziquantel can be decreased when combined with Osilodrostat.
Melatonin The metabolism of Melatonin can be decreased when combined with Osilodrostat.
Primaquine The metabolism of Osilodrostat can be decreased when combined with Primaquine.
Hesperetin The metabolism of Hesperetin can be decreased when combined with Osilodrostat.
Leflunomide The metabolism of Leflunomide can be decreased when combined with Osilodrostat.
Nifedipine The metabolism of Nifedipine can be decreased when combined with Osilodrostat.
Carvedilol The metabolism of Carvedilol can be decreased when combined with Osilodrostat.
Doxepin The metabolism of Doxepin can be decreased when combined with Osilodrostat.
Propafenone The metabolism of Propafenone can be decreased when combined with Osilodrostat.
Domperidone The metabolism of Domperidone can be decreased when combined with Osilodrostat.
Dexfenfluramine The metabolism of Dexfenfluramine can be decreased when combined with Osilodrostat.
Metoclopramide The metabolism of Metoclopramide can be decreased when combined with Osilodrostat.
Oxtriphylline The metabolism of Oxtriphylline can be decreased when combined with Osilodrostat.
Rasagiline The metabolism of Rasagiline can be decreased when combined with Osilodrostat.
Temafloxacin The metabolism of Temafloxacin can be decreased when combined with Osilodrostat.
Theobromine The metabolism of Theobromine can be decreased when combined with Osilodrostat.
Aminophenazone The metabolism of Aminophenazone can be decreased when combined with Osilodrostat.
Antipyrine The metabolism of Antipyrine can be decreased when combined with Osilodrostat.

Target Protein

Cytochrome P450 11B1, mitochondrial CYP11B1
Cytochrome P450 11B2, mitochondrial CYP11B2

Referensi & Sumber

Artikel (PubMed)
  • PMID: 28155129
    Armani S, Ting L, Sauter N, Darstein C, Tripathi AP, Wang L, Zhu B, Gu H, Chun DY, Einolf HJ, Kulkarni S: Drug Interaction Potential of Osilodrostat (LCI699) Based on Its Effect on the Pharmacokinetics of Probe Drugs of Cytochrome P450 Enzymes in Healthy Adults. Clin Drug Investig. 2017 May;37(5):465-472. doi: 10.1007/s40261-017-0497-0.
  • PMID: 25953419
    Papillon JP, Adams CM, Hu QY, Lou C, Singh AK, Zhang C, Carvalho J, Rajan S, Amaral A, Beil ME, Fu F, Gangl E, Hu CW, Jeng AY, LaSala D, Liang G, Logman M, Maniara WM, Rigel DF, Smith SA, Ksander GM: Structure-Activity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors. J Med Chem. 2015 Jun 11;58(11):4749-70. doi: 10.1021/acs.jmedchem.5b00407. Epub 2015 May 21.
  • PMID: 27481775
    Weldon SM, Cerny MA, Gueneva-Boucheva K, Cogan D, Guo X, Moss N, Parmentier JH, Richman JR, Reinhart GA, Brown NF: Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates. J Pharmacol Exp Ther. 2016 Oct;359(1):142-50. doi: 10.1124/jpet.116.236463. Epub 2016 Aug 1.
  • PMID: 32141023
    Duggan S: Osilodrostat: First Approval. Drugs. 2020 Mar 5. pii: 10.1007/s40265-020-01277-0. doi: 10.1007/s40265-020-01277-0.
  • PMID: 23535464
    Prague JK, May S, Whitelaw BC: Cushing's syndrome. BMJ. 2013 Mar 27;346:f945. doi: 10.1136/bmj.f945.

Contoh Produk & Brand

Produk: 6 • International brands: 0
Produk
  • Isturisa
    Tablet, coated • 1 mg/1 • Oral • US • Approved
  • Isturisa
    Tablet, coated • 5 mg/1 • Oral • US • Approved
  • Isturisa
    Tablet, coated • 10 mg/1 • Oral • US • Approved
  • Isturisa
    Tablet, film coated • 1 mg • Oral • EU • Approved
  • Isturisa
    Tablet, film coated • 5 mg • Oral • EU • Approved
  • Isturisa
    Tablet, film coated • 10 mg • Oral • EU • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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