Isavuconazole

J02A - Antimycotics for systemic use ATC J02AC05 Small molecule

JFDA label: Cresemba

Mechanism of Action

Isavuconazonium sulfate is a prodrug that is rapidly hydrolyzed in the blood to active isavuconazole. Isavuconazole inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase. This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weakens the membrane structure and function.

Indications

Approved

Aspergillosis
Mucormycosis

Class profile

antifungalClass	Azole (extended-spectrum)
targetMolecule	Lanosterol 14-alpha-demethylase (CYP51)
isFungicidal	0
spectrumCandida	S
spectrumAspergillus	S (including resistant Aspergillus strains partially)
spectrumCryptococcus	S
spectrumDermatophytes	Limited
resistanceMechanisms	CYP51A mutations (Cyp51A G54/G138 in Aspergillus)
source	Pappas2016/Lass-Florl2011

Contraindications

Source: Lexicomp

Hypersensitivity to isavuconazonium sulfate (eg, isavuconazole) or any component of the formulation Absolute
concurrent use of strong CYP3A4 inducers (eg, rifampin, carbamazepine, St. John’s wort, long acting barbiturates) Absolute
concurrent use of strong CYP3A4 inhibitors (eg, ketoconazole, high-dose ritonavir [400 mg every 12 hours]) Absolute
familial short QT syndrome Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Very Common Peripheral edema

Common atrial fibrillation, anxiety, brain disease, pruritus, alopecia, hypoalbuminemia, dyspepsia, abdominal distention, increased serum AST, hepatic failure, increased serum transaminases · Chest pain · hypotension

Nervous system disorders (3)

Very Common fatigue · Headache · insomnia

Hepatobiliary disorders (1)

Very Common Increased liver enzymes

Immune system disorders (1)

Common Hypersensitivity

Metabolism and nutrition disorders (1)

Very Common Hypokalemia

Gastrointestinal disorders (5)

Very Common abdominal pain · constipation · diarrhea · Nausea · vomiting

Musculoskeletal and connective tissue disorders (2)

Common Back pain · myositis, bronchospasm (

Respiratory, thoracic and mediastinal disorders (2)

Very Common cough · Dyspnea

Dosing

Source: Lexicomp

Note: Dosage expressed as milligrams of isavuconazonium sulfate; switching between the intravenous (IV) and oral formulations of isavuconazonium sulfate is acceptable; for maintenance dosing, it is not necessary to restart dosing with the initial dose regimen when switching between formulations. Aspergillosis, invasive: IV: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose. Oral: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose. Duration of therapy: Minimum of 6 to 12 weeks, although duration is highly dependent on degree/duration of immunosuppression, disease site, and evidence of disease improvement (IDSA [Patterson 2016]) Mucormycosis, invasive: IV: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose. Oral: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.

Refer to adult dosing.

No dosage adjustment necessary.

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary. Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

Warnings & Precautions

Source: Lexicomp

Hepatic effects

Severe reactions (hepatic failure [including fatalities], hepatitis, and cholestasis) have been reported in patients with serious underlying medical conditions (eg, hematologic malignancy). Other reactions (elevations in AST, ALT, alkaline phosphatase and total bilirubin) have also been reported; these elevations are generally reversible and do not require discontinuation of therapy. Monitor liver function tests at baseline and periodically during therapy. If abnormal liver function tests develop, monitor closely for development of severe hepatic reactions. Discontinue therapy if clinical signs and symptoms of liver disease develop.

Hypersensitivity

Serious hypersensitivity (eg, anaphylaxis) and severe skin reactions (eg, Stevens-Johnson syndrome) have been reported with other azole antifungal agents. Discontinue if a severe skin reaction occurs. There is no information regarding cross-sensitivity between isavuconazonium sulfate and other azoles. Use with caution in patients with hypersensitivity reactions to other azoles. Disease-related concerns:

Hepatic impairment

Use with caution and monitor for adverse effects in patients with severe hepatic impairment (Child-Pugh class C). Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Drug particulates

Following dilution for IV infusion, may form precipitate from the insoluble isavuconazole. Use an infusion set with an in-line filter (pore size 0.2 to 1.2 micron) for IV administration.

Infusion-related reactions

Infusion reactions (eg, hypotension, dizziness, chills, dyspnea, paresthesia and hypoesthesia) have been reported during IV administration. Discontinue the infusion if these reactions occur.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events were observed in animal reproduction studies. Based on animal data, isavuconazonium sulfate may have the potential to increase the risk of adverse developmental events if used in pregnant women.

Lactation

Avoid

It is not known if isavuconazonium sulfate is excreted into breast milk. Breast-feeding is not recommended by the manufacturer.

Monitoring

Efficacy	Fungal culture and species identification; minimum inhibitory concentration (MIC) where available; clinical response (temperature, imaging for invasive fungal disease)
Toxicity	LFTs (hepatotoxicity — azoles in particular); renal function; ECG for QT prolongation (azoles); drug levels if available (itraconazole, voriconazole)
Clinical pearl	Voriconazole levels are highly variable due to CYP2C19 polymorphism — TDM recommended (target trough 2–5 mg/L). Check for drug interactions with CYP3A4 substrates.
Counseling	Report visual disturbances (voriconazole), jaundice, or rash. Take azoles with food or as directed to optimise absorption.

Chemistry & Properties

Formula	C22H17F2N5OS
Molecular weight	437.48 g/mol
IUPAC name	4-[2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl]benzonitrile
CAS	241479-67-4
PubChem CID	6918485
InChIKey	`DDFOUSQFMYRUQK-RCDICMHDSA-N`
logP	4.24 (XLogP 3.5)
Polar surface area	87.62 Å²
H-bond acceptors / donors	7 / 1
Drug-likeness (QED)	0.49
Lipinski violations	0

SMILES

C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	0.77 h
Volume of distribution	6.519 L/kg
Protein binding	99.7%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Cresemba	Vial 200 mg	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Cresemba	Capsule 100 mg	14 cap	Hikma Pharmaceuticals Co.Ltd/Jordan	—