Peringatan Keamanan

Toxicity information regarding levoketoconazole is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nausea, vomiting, hypokalemia, hemorrhage, systemic hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, and peripheral edema. Symptomatic and supportive measures are recommended; within the first hour following ingestion, activated charcoal may be beneficial.L39563

Levoketoconazole

DB05667

small molecule approved investigational

Deskripsi

Cushing's syndrome (CS) is underpinned by chronic hypercortisolism leading to multisystem morbidity, including effects on the cardiovascular and endocrine systems, metabolic syndrome with accompanying changes in body composition, neuropsychiatric effects, changes in blood pressure and chemistry, and opportunistic infections.A244078, A244083 Ketoconazole has been used both on- and off-label to treat CS due to its ability to inhibit cortisol production. Still, toxicity has limited its use, notably hepatic toxicity and a tendency to prolong the QT interval.A244083 Levoketoconazole is one of two enantiomers present in racemic ketoconazole. It possesses most of the inhibitory effect towards steroidogenic enzymes, making it an attractive candidate for CS treatment with a potentially lower toxicity profile than its racemate.A244083, A29319, L39573

Levoketoconazole was approved by the FDA on December 30, 2021, and is currently marketed under the registered trademark RECORLEV by Xeris Pharmaceuticals, Inc.L39563

Struktur Molekul 2D

Berat 531.431
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Levoketoconazole has a plasma elimination half-life of 3-4.5 hours following a single dose and 4-6 hours following multiple doses.[L39563]
Volume Distribusi Levoketoconazole has an apparent volume of distribution of 31-41 L, approximating total body water.[L39563]
Klirens (Clearance) -

Absorpsi

Levoketoconazole has a Tmax of ~1.5-2 hours regardless of dose, while the Cmax increases proportionally with the dose. The AUC increases greater than dose proportionally over the recommended range of 150-600 mg. Co-administration of a single 600 mg oral dose with a high-fat meal increased the AUC by 30% with no change in Cmax and a delay in the median Tmax from two to four hours. The pharmacokinetics of racemic ketoconazole are not significantly different in patients with renal impairment; given the extensive hepatic metabolism of ketoconazole, it is expected that hepatic impairment will affect the pharmacokinetics of levoketoconazole.L39563

Metabolisme

No in vitro or in vivo studies of levoketoconazole metabolism have been performed. Ketoconazole is known to be hepatically metabolized to several inactive metabolites, mainly through oxidation of the imidazole and piperazine rings, together with oxidative O-dealkylation and aromatic hydroxylation.L39563 Levoketoconazole is known to both induce and strongly inhibit CYP3A4.A23103, A244088, L39563

Rute Eliminasi

Approximately 13% of racemic ketoconazole is excreted in the urine, 2-4% as unchanged drug, while the major excretion route is in the feces, accounting for ~57%.L39563

Interaksi Makanan

2 Data
  • 1. Avoid excessive or chronic alcohol consumption. Concomitant alcohol consumption may result in a disulfiram-like reaction characterized by rash, flushing, peripheral edema, nausea, and headache. These symptoms typically subside within hours.
  • 2. Take with or without food. In healthy subjects administered a single 600 mg oral dose of levoketoconazole, a high-fat meal increased the AUC by 30% with no change in the maximum plasma concentration but a delay to reach this value of between two and four hours. These changes are not considered clinically significant.

Interaksi Obat

979 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Levoketoconazole.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Levoketoconazole.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be increased when it is combined with Levoketoconazole.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Levoketoconazole.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Levoketoconazole.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Levoketoconazole.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Levoketoconazole.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Levoketoconazole.
Ranolazine The metabolism of Ranolazine can be decreased when combined with Levoketoconazole.
Silodosin The excretion of Silodosin can be decreased when combined with Levoketoconazole.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Levoketoconazole.
Amphotericin B The therapeutic efficacy of Amphotericin B can be decreased when used in combination with Levoketoconazole.
Didanosine Didanosine can cause a decrease in the absorption of Levoketoconazole resulting in a reduced serum concentration and potentially a decrease in efficacy.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Levoketoconazole.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Levoketoconazole.
Everolimus The serum concentration of Everolimus can be increased when it is combined with Levoketoconazole.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Levoketoconazole.
Sildenafil The serum concentration of Sildenafil can be increased when it is combined with Levoketoconazole.
Cilostazol The metabolism of Cilostazol can be decreased when combined with Levoketoconazole.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Levoketoconazole.
Fentanyl The metabolism of Fentanyl can be decreased when combined with Levoketoconazole.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Levoketoconazole.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Levoketoconazole.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Levoketoconazole.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Levoketoconazole.
Eszopiclone The serum concentration of Eszopiclone can be increased when it is combined with Levoketoconazole.
Zopiclone The metabolism of Zopiclone can be decreased when combined with Levoketoconazole.
Lovastatin The serum concentration of Lovastatin can be increased when it is combined with Levoketoconazole.
Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Levoketoconazole.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Levoketoconazole.
Sucralfate Sucralfate can cause a decrease in the absorption of Levoketoconazole resulting in a reduced serum concentration and potentially a decrease in efficacy.
Warfarin The metabolism of Warfarin can be decreased when combined with Levoketoconazole.
Acenocoumarol The metabolism of Acenocoumarol can be decreased when combined with Levoketoconazole.
(R)-warfarin The metabolism of (R)-warfarin can be decreased when combined with Levoketoconazole.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Levoketoconazole.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Levoketoconazole.
(S)-Warfarin The metabolism of (S)-Warfarin can be decreased when combined with Levoketoconazole.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Levoketoconazole.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Levoketoconazole.
Atorvastatin The metabolism of Atorvastatin can be decreased when combined with Levoketoconazole.
Vincristine The excretion of Vincristine can be decreased when combined with Levoketoconazole.
Doxorubicin The serum concentration of Doxorubicin can be increased when it is combined with Levoketoconazole.
Betrixaban The serum concentration of Betrixaban can be increased when it is combined with Levoketoconazole.
Isradipine The metabolism of Isradipine can be decreased when combined with Levoketoconazole.
Trimethadione The metabolism of Trimethadione can be decreased when combined with Levoketoconazole.
Amlodipine The metabolism of Amlodipine can be decreased when combined with Levoketoconazole.
Nimodipine The metabolism of Nimodipine can be decreased when combined with Levoketoconazole.
Cinnarizine The metabolism of Cinnarizine can be decreased when combined with Levoketoconazole.
Ethosuximide The metabolism of Ethosuximide can be decreased when combined with Levoketoconazole.
Nicardipine The metabolism of Nicardipine can be decreased when combined with Levoketoconazole.
Magnesium sulfate The therapeutic efficacy of Levoketoconazole can be increased when used in combination with Magnesium sulfate.
Perhexiline The metabolism of Perhexiline can be decreased when combined with Levoketoconazole.
Carvedilol The metabolism of Carvedilol can be decreased when combined with Levoketoconazole.
Bepridil The metabolism of Bepridil can be decreased when combined with Levoketoconazole.
Nimesulide The metabolism of Nimesulide can be decreased when combined with Levoketoconazole.
Prenylamine The metabolism of Prenylamine can be decreased when combined with Levoketoconazole.
Cyclandelate The metabolism of Cyclandelate can be decreased when combined with Levoketoconazole.
Flunarizine The metabolism of Flunarizine can be decreased when combined with Levoketoconazole.
Fluspirilene The metabolism of Fluspirilene can be decreased when combined with Levoketoconazole.
Clevidipine The metabolism of Clevidipine can be decreased when combined with Levoketoconazole.
Methsuximide The therapeutic efficacy of Levoketoconazole can be increased when used in combination with Methsuximide.
Seletracetam The metabolism of Seletracetam can be decreased when combined with Levoketoconazole.
Nylidrin The metabolism of Nylidrin can be decreased when combined with Levoketoconazole.
Ziconotide The therapeutic efficacy of Levoketoconazole can be increased when used in combination with Ziconotide.
Dotarizine The metabolism of Dotarizine can be decreased when combined with Levoketoconazole.
Xylometazoline The therapeutic efficacy of Levoketoconazole can be increased when used in combination with Xylometazoline.
Nilvadipine The metabolism of Nilvadipine can be decreased when combined with Levoketoconazole.
Tranilast The metabolism of Tranilast can be decreased when combined with Levoketoconazole.
Fasudil The therapeutic efficacy of Levoketoconazole can be increased when used in combination with Fasudil.
Agmatine The metabolism of Agmatine can be decreased when combined with Levoketoconazole.
Fendiline The metabolism of Fendiline can be decreased when combined with Levoketoconazole.
Eperisone The metabolism of Eperisone can be decreased when combined with Levoketoconazole.
Trimebutine The metabolism of Trimebutine can be decreased when combined with Levoketoconazole.
Pinaverium The metabolism of Pinaverium can be decreased when combined with Levoketoconazole.
Barnidipine The metabolism of Barnidipine can be decreased when combined with Levoketoconazole.
Aranidipine The metabolism of Aranidipine can be decreased when combined with Levoketoconazole.
Azelnidipine The metabolism of Azelnidipine can be decreased when combined with Levoketoconazole.
Cilnidipine The metabolism of Cilnidipine can be decreased when combined with Levoketoconazole.
Darodipine The metabolism of Darodipine can be decreased when combined with Levoketoconazole.
Efonidipine The metabolism of Efonidipine can be decreased when combined with Levoketoconazole.
Lacidipine The metabolism of Lacidipine can be decreased when combined with Levoketoconazole.
Manidipine The metabolism of Manidipine can be decreased when combined with Levoketoconazole.
Niguldipine The metabolism of Niguldipine can be decreased when combined with Levoketoconazole.
Niludipine The metabolism of Niludipine can be decreased when combined with Levoketoconazole.
Carboxyamidotriazole The metabolism of Carboxyamidotriazole can be decreased when combined with Levoketoconazole.
Naftopidil The metabolism of Naftopidil can be decreased when combined with Levoketoconazole.
Tetrahydropalmatine The metabolism of Tetrahydropalmatine can be decreased when combined with Levoketoconazole.
Vinpocetine The metabolism of Vinpocetine can be decreased when combined with Levoketoconazole.
Gallopamil The metabolism of Gallopamil can be decreased when combined with Levoketoconazole.
Bencyclane The metabolism of Bencyclane can be decreased when combined with Levoketoconazole.
Otilonium The metabolism of Otilonium can be decreased when combined with Levoketoconazole.
Terodiline The metabolism of Terodiline can be decreased when combined with Levoketoconazole.
Lidoflazine The metabolism of Lidoflazine can be decreased when combined with Levoketoconazole.
Penfluridol The metabolism of Penfluridol can be decreased when combined with Levoketoconazole.
Caroverine The metabolism of Caroverine can be decreased when combined with Levoketoconazole.
WIN 55212-2 The metabolism of WIN 55212-2 can be decreased when combined with Levoketoconazole.
Fish oil The metabolism of Fish oil can be decreased when combined with Levoketoconazole.
Dexverapamil The metabolism of Dexverapamil can be decreased when combined with Levoketoconazole.
Emopamil The metabolism of Emopamil can be decreased when combined with Levoketoconazole.
Lomerizine The metabolism of Lomerizine can be decreased when combined with Levoketoconazole.

Target Protein

Steroid 17-alpha-hydroxylase/17,20 lyase CYP17A1
Cytochrome P450 11B1, mitochondrial CYP11B1
Cytochrome P450 11B2, mitochondrial CYP11B2
Cholesterol side-chain cleavage enzyme, mitochondrial CYP11A1
Lanosterol 14-alpha demethylase CYP51A1

Referensi & Sumber

Synthesis reference: Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25.
Artikel (PubMed)
  • PMID: 30033041
    Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A: Advances in the medical treatment of Cushing's syndrome. Lancet Diabetes Endocrinol. 2019 Apr;7(4):300-312. doi: 10.1016/S2213-8587(18)30155-4. Epub 2018 Jul 20.
  • PMID: 34380370
    Fleseriu M, Auchus RJ, Pivonello R, Salvatori R, Zacharieva S, Biller BMK: Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. Expert Rev Endocrinol Metab. 2021 Jul;16(4):159-174. doi: 10.1080/17446651.2021.1945440. Epub 2021 Aug 12.
  • PMID: 1495014
    Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25.
  • PMID: 25343516
    Novotna A, Krasulova K, Bartonkova I, Korhonova M, Bachleda P, Anzenbacher P, Dvorak Z: Dual effects of ketoconazole cis-enantiomers on CYP3A4 in human hepatocytes and HepG2 Cells. PLoS One. 2014 Oct 24;9(10):e111286. doi: 10.1371/journal.pone.0111286. eCollection 2014.
  • PMID: 14712470
    Dilmaghanian S, Gerber JG, Filler SG, Sanchez A, Gal J: Enantioselectivity of inhibition of cytochrome P450 3A4 (CYP3A4) by ketoconazole: Testosterone and methadone as substrates. Chirality. 2004 Feb;16(2):79-85. doi: 10.1002/chir.10294.

Contoh Produk & Brand

Produk: 1 • International brands: 0
Produk
  • Recorlev
    Tablet • 150 mg/1 • Oral • US • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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