Peringatan Keamanan

At three times the recommended maintenance dose of isavuconazole, treatment-emergent adverse reactions included headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. As there is no specific antidote or effective method of hemodialysis for isavuconazole, supportive treatment with appropriate monitoring is recommended in case of overdose FDA Label.

No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats FDA Label. However, isavuconazole was weakly clastogenic at cytotoxic concentrations in the L5178Y tk+/- mouse lymphoma chromosome aberration assay without any significant evidence of increased frequency of micronuclei in an in vivo rat micronucleus test L1482. While carcinogenicity studies isavuconazole have not been performed, other drugs in the azole class at near human recommended doses were associated with the development of hepatocellular adenomas and carcinomas in mice and rat carcinogenicity studies FDA Label. At doses up to 90 mg/kg/day, oral isavuconazole did not affect the fertility in male or female rats. Isavuconazole at systemic exposures of subtherapeutic levels was associated with dose-related increases in the incidence of skeletal anomalies in rat and rabbit offsprings L1482. In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in offspring L1482.

Isavuconazole

DB11633

small molecule approved investigational

Deskripsi

Isavuconazole is an triazole antifungal with broad spectrum of activity and good safety profile A32026. It is approved by the FDA and EMA for the treatment of invasive aspergillosis and mucormycosis. It works by inhibiting fungal cell membrane synthesis. Invasive fungal infections pose significant clinical challenges for patients, especially those who are immunocompromised. In vitro, most of the Candida species, most Aspergillus species, Mucorales, Cryptococcus spp., Fusarium species, dermatophytes and dimorphic fungi displayed susceptibility to isavuconzaole A32029. Resistance to isavuconazole has been associated with the mutation in the target gene CYP51 FDA Label. Cross-resistance between isavuconazole and other azoles was also proposed although the clinical relevance is unclear FDA Label.

As isavuconazole displays low water solubility, it is found as an active ingredient of its prodrug, DB06636. The prodrug formulation of isavuconazole is FDA- and EMA-approved and is marketed under the trade name Cresemba for the treatment of invasive aspergillosis and mucormycosis as oral or intravenous administration. The intravenous formulation is cyclodextrin-free which gives isavuconazole an advantage over other azole antifungals that requires cyclodextrin for facilitating drug solubility; this is because cyclodextrin has a potential for nephrotoxicity A32029. It is proposed that the intravenous and oral dosing can be used interchangeably L1482, without the need for a repeat loading dose when transitioning from an IV to an oral formulation A32026. Isavuconazonium displays excellent water solubility for intravenous formulations, good absorption, and enhanced oral bioavailability A32026. Following administration, isavuconazonium undergoes biotransformation to form the active moiety, isavuconazole, for the antifungal actions.

Struktur Molekul 2D

Berat 437.47
Wujud -

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours [FDA label]. The mean half life following oral and intravenous administration of 400 mg isavuconazole was 110 and 115 hours, respectively [L1482].
Volume Distribusi The mean steady state volume of distribution (Vss) was approximately 450 L following intravenous administration [FDA Label].
Klirens (Clearance) The clearance (CL) rate was 2.5 ± 1.6 L/h in patients receiving 200 mg isavuconazole orally or intravenously [A32028].

Absorpsi

Following oral administration of 200 mg isavuconazole, the mean peak plasma concentration (Cmax) at steady state was 7499 ng/mL. Cmax following oral administration of 600 mg isavuconazole was 20028 ng/mL FDA Label. It is proposed that the Cmax at steady state is reached approximately 2–3 hours after single and multiple dosing of isavuconazole FDA Label. Administration of 400 mg of oral and intravenous isavuconazole resulted in mean AUC of 189462.8 h*ng/mL and 193906.8 h*ng/mL, respectively L1482. While isavuconazole can be administered with or without food, concurrent consumption of a high-fat meal reduced oral isavuconazole Cmax by 9% and increased AUC by 9% FDA Label. The absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98% FDA Label.

Metabolisme

Following rapid conversion of the prodrug isavuconazonium to isavuconazole via esterase-mediated hydrolysis, a number of minor metabolites were identified in addition to the active moiety itself and the inactive cleavage product of isavuconazonium. However, no individual metabolite was observed with an AUC greater than 10% of total radio-labeled material FDA label. The main enzymes involved in the metabolism of isavuconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT) according to the findings of in vivo and in vitro studies FDA Label.

Rute Eliminasi

Following oral administration, 46.1% of total radiolabelled isavuconzaole was detected in the feces, and about 45.5% was recovered in urine FDA Label. Unchanged isavuconazole in the urine was less than 1% of the total dose administered FDA Label.

Interaksi Makanan

2 Data
  • 1. Avoid St. John's Wort.
  • 2. Exercise caution with grapefruit products.

Interaksi Obat

1237 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Isavuconazole.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Isavuconazole.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be increased when it is combined with Isavuconazole.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Isavuconazole.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Isavuconazole.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Isavuconazole.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Isavuconazole.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Isavuconazole.
Silodosin The excretion of Silodosin can be decreased when combined with Isavuconazole.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Isavuconazole.
Aripiprazole The metabolism of Aripiprazole can be increased when combined with Isavuconazole.
Aripiprazole lauroxil The metabolism of Aripiprazole lauroxil can be increased when combined with Isavuconazole.
Fosphenytoin The metabolism of Isavuconazole can be increased when combined with Fosphenytoin.
Phenytoin The metabolism of Isavuconazole can be increased when combined with Phenytoin.
Cilostazol The serum concentration of Cilostazol can be increased when it is combined with Isavuconazole.
Amphotericin B The therapeutic efficacy of Amphotericin B can be decreased when used in combination with Isavuconazole.
Brexpiprazole The metabolism of Brexpiprazole can be decreased when combined with Isavuconazole.
Didanosine Didanosine can cause a decrease in the absorption of Isavuconazole resulting in a reduced serum concentration and potentially a decrease in efficacy.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Isavuconazole.
Everolimus The metabolism of Everolimus can be decreased when combined with Isavuconazole.
Flibanserin The metabolism of Flibanserin can be decreased when combined with Isavuconazole.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Isavuconazole.
Ivabradine The metabolism of Ivabradine can be decreased when combined with Isavuconazole.
Ivacaftor The metabolism of Ivacaftor can be decreased when combined with Isavuconazole.
Lurasidone The metabolism of Lurasidone can be decreased when combined with Isavuconazole.
Olaparib The metabolism of Olaparib can be decreased when combined with Isavuconazole.
Sonidegib The metabolism of Sonidegib can be decreased when combined with Isavuconazole.
Avanafil The metabolism of Avanafil can be decreased when combined with Isavuconazole.
Eplerenone The metabolism of Eplerenone can be decreased when combined with Isavuconazole.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Isavuconazole.
Sildenafil The serum concentration of Sildenafil can be increased when it is combined with Isavuconazole.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Isavuconazole.
Fentanyl The metabolism of Fentanyl can be decreased when combined with Isavuconazole.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Isavuconazole.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Isavuconazole.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Isavuconazole.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Isavuconazole.
Zopiclone The metabolism of Zopiclone can be decreased when combined with Isavuconazole.
Lovastatin The metabolism of Lovastatin can be decreased when combined with Isavuconazole.
Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Isavuconazole.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Isavuconazole.
Atomoxetine The metabolism of Atomoxetine can be decreased when combined with Isavuconazole.
Sucralfate Sucralfate can cause a decrease in the absorption of Isavuconazole resulting in a reduced serum concentration and potentially a decrease in efficacy.
Ifosfamide The metabolism of Ifosfamide can be increased when combined with Isavuconazole.
Perampanel The metabolism of Perampanel can be increased when combined with Isavuconazole.
Warfarin The serum concentration of Warfarin can be increased when it is combined with Isavuconazole.
Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Isavuconazole.
(R)-warfarin The serum concentration of (R)-warfarin can be increased when it is combined with Isavuconazole.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Isavuconazole.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Isavuconazole.
(S)-Warfarin The serum concentration of (S)-Warfarin can be increased when it is combined with Isavuconazole.
Atorvastatin The metabolism of Atorvastatin can be decreased when combined with Isavuconazole.
Vincristine The excretion of Vincristine can be decreased when combined with Isavuconazole.
Doxorubicin The serum concentration of Doxorubicin can be increased when it is combined with Isavuconazole.
Erlotinib The serum concentration of Erlotinib can be decreased when it is combined with Isavuconazole.
Bexarotene The metabolism of Isavuconazole can be increased when combined with Bexarotene.
Bosentan The metabolism of Isavuconazole can be increased when combined with Bosentan.
Nafcillin The metabolism of Isavuconazole can be increased when combined with Nafcillin.
Modafinil The metabolism of Isavuconazole can be increased when combined with Modafinil.
Etravirine The metabolism of Isavuconazole can be increased when combined with Etravirine.
Avasimibe The metabolism of Isavuconazole can be increased when combined with Avasimibe.
Echinacea The metabolism of Isavuconazole can be increased when combined with Echinacea.
Dexamethasone acetate The metabolism of Isavuconazole can be increased when combined with Dexamethasone acetate.
Cobimetinib The metabolism of Cobimetinib can be decreased when combined with Isavuconazole.
Betrixaban The serum concentration of Betrixaban can be increased when it is combined with Isavuconazole.
Tipiracil The excretion of Tipiracil can be decreased when combined with Isavuconazole.
Magnesium sulfate The therapeutic efficacy of Isavuconazole can be increased when used in combination with Magnesium sulfate.
Xylometazoline The therapeutic efficacy of Isavuconazole can be increased when used in combination with Xylometazoline.
Fasudil The therapeutic efficacy of Isavuconazole can be increased when used in combination with Fasudil.
Ziconotide The therapeutic efficacy of Isavuconazole can be increased when used in combination with Ziconotide.
Pitolisant The serum concentration of Isavuconazole can be decreased when it is combined with Pitolisant.
Ritonavir The serum concentration of Isavuconazole can be increased when it is combined with Ritonavir.
Lopinavir The serum concentration of Isavuconazole can be increased when it is combined with Lopinavir.
Cyclosporine The serum concentration of Cyclosporine can be increased when it is combined with Isavuconazole.
Sirolimus The serum concentration of Sirolimus can be increased when it is combined with Isavuconazole.
Temsirolimus The serum concentration of Temsirolimus can be increased when it is combined with Isavuconazole.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Isavuconazole.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Isavuconazole.
Mycophenolic acid The serum concentration of Mycophenolic acid can be increased when it is combined with Isavuconazole.
Mycophenolate mofetil The serum concentration of Mycophenolate mofetil can be increased when it is combined with Isavuconazole.
Pravastatin The serum concentration of Pravastatin can be increased when it is combined with Isavuconazole.
Morphine The serum concentration of Morphine can be increased when it is combined with Isavuconazole.
Tenofovir disoproxil The serum concentration of Tenofovir disoproxil can be increased when it is combined with Isavuconazole.
Clobazam The serum concentration of Clobazam can be increased when it is combined with Isavuconazole.
Quinine The serum concentration of Quinine can be increased when it is combined with Isavuconazole.
Toremifene The serum concentration of Toremifene can be increased when it is combined with Isavuconazole.
Vinblastine The serum concentration of Vinblastine can be increased when it is combined with Isavuconazole.
Bisoprolol The serum concentration of Bisoprolol can be increased when it is combined with Isavuconazole.
Simvastatin The serum concentration of Simvastatin can be increased when it is combined with Isavuconazole.
Mannitol The serum concentration of Mannitol can be increased when it is combined with Isavuconazole.
Etoposide The serum concentration of Etoposide can be increased when it is combined with Isavuconazole.
Clomifene The serum concentration of Clomifene can be increased when it is combined with Isavuconazole.
Quinidine The serum concentration of Quinidine can be increased when it is combined with Isavuconazole.
Fexofenadine The serum concentration of Fexofenadine can be increased when it is combined with Isavuconazole.
Dactinomycin The serum concentration of Dactinomycin can be increased when it is combined with Isavuconazole.
Tegaserod The serum concentration of Tegaserod can be increased when it is combined with Isavuconazole.
Dasatinib The serum concentration of Dasatinib can be increased when it is combined with Isavuconazole.
Sitagliptin The serum concentration of Sitagliptin can be increased when it is combined with Isavuconazole.
Paliperidone The serum concentration of Paliperidone can be increased when it is combined with Isavuconazole.
Digitoxin The serum concentration of Digitoxin can be increased when it is combined with Isavuconazole.

Target Protein

Lanosterol 14-alpha demethylase ERG11
Voltage-gated inwardly rectifying potassium channel KCNH2 KCNH2
Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C
G protein-activated inward rectifier potassium channel 2 KCNJ6
G protein-activated inward rectifier potassium channel 3 KCNJ9
ATP-sensitive inward rectifier potassium channel 11 KCNJ11
Potassium voltage-gated channel subfamily A member 5 KCNA5
A-type voltage-gated potassium channel KCND3 KCND3
Potassium voltage-gated channel subfamily KQT member 1 KCNQ1
Sodium channel protein type 5 subunit alpha SCN5A

Referensi & Sumber

Artikel (PubMed)
  • PMID: 27330318
    Donnelley MA, Zhu ES, Thompson GR 3rd: Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections. Infect Drug Resist. 2016 Jun 2;9:79-86. doi: 10.2147/IDR.S81416. eCollection 2016.
  • PMID: 27185799
    Kovanda LL, Desai AV, Lu Q, Townsend RW, Akhtar S, Bonate P, Hope WW: Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study). Antimicrob Agents Chemother. 2016 Jul 22;60(8):4568-76. doi: 10.1128/AAC.00514-16. Print 2016 Aug.
  • PMID: 24187505
    Falci DR, Pasqualotto AC: Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013 Oct 22;6:163-74. doi: 10.2147/IDR.S51340.

Contoh Produk & Brand

Produk: 3 • International brands: 0
Produk
  • Cresemba
    Capsule • 40 mg • Oral • EU • Approved
  • Cresemba
    Injection, powder, for solution • 200 mg • Intravenous • EU • Approved
  • Cresemba
    Capsule • 100 mg • Oral • EU • Approved

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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