Isavuconazonium, sold under the brand name Cresemba, is a systemic

antifungal medication An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cry ...

of the

triazole A triazole is a heterocyclic compound featuring a five-membered ring of two carbon atoms and three nitrogen atoms with molecular formula C2H3N3. Triazoles exhibit substantial Isomer, isomerism, depending on the positioning of the nitrogen atoms w ...

class which is used to treat invasive

aspergillosis Aspergillosis is a fungal infection of usually the lungs, caused by the genus ''Aspergillus'', a common mold that is breathed in frequently from the air, but does not usually affect most people. It generally occurs in people with lung diseases su ...

and

mucormycosis Mucormycosis, also known as black fungus, is a severe fungal infection that comes under fulminant fungal sinusitis, usually in people who are immunocompromised. It is curable only when diagnosed early. Symptoms depend on where in the body the ...

. It is used as the sulfate. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

or given via

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

. The most common side effects include abnormal liver enzyme tests, nausea, vomiting, difficulty breathing, abdominal pain, diarrhea, injection site reactions, headache,

low blood potassium Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an ab ...

, and skin rash. Isavuconazonium is a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

of isavuconazole.

Medical uses

Isavuconazonium is used to treat invasive

and invasive

in adults aged eighteen years and older. It is available in a capsule for administration by mouth and as a powder for administration via infusion.

Contraindications

Isavuconazonium is contraindicated in people taking strong

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

inhibitors, strong

inducers, or moderate CYP3A4 or

CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the ''CYP3A5'' gene. Tissue distribution ''CYP3A5'' encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the ...

inducers. It is contraindicated in people with familial short QT syndrome.

Side effects

Common adverse effects (occurring in between 1 and 10% of people) include

low potassium Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an ab ...

, decreased appetite, delirium, headache, sleepiness, vein inflammation, difficulty breathing, acute respiratory failure, vomiting, diarrhea, nausea, stomach pain, elevated results in

liver function tests Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial ...

, rash, itchy skin, kidney failure, chest pain, and fatigue. There are several uncommon side effects as well. In preclinical studies, isavuconazonium caused birth defects in animals; it has not been tested in pregnant women.

Interactions

Isavuconazonium is converted into isavuconazole inside the body, and isavuconazole is a substrate for

. Many other medications inhibit or induce those two enzymes, and isavuconazonium should not be administered with them. Inducers result in levels of isavuconazole that are too low and will not work. Inhibitors can cause high levels of isavuconazole, which will, in turn, cause increased adverse events and toxicity. Likewise, isavuconazonium can interfere with the appropriate dosing of other drugs that are substrates for those enzymes. In addition, isavuconazole induces

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Func ...

and can decrease the amount of drugs metabolized by the enzyme. Isavuconazole inhibits

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

(P-gp),

BCRP ATP-binding cassette super-family G member 2 is a protein that in humans is encoded by the ''ABCG2'' gene. ABCG2 has also been designated as CDw338 (cluster of differentiation w338). ABCG2 is a translocation protein used to actively pump drugs ...

SLC22A2 Solute carrier family 22 member 2 (also termed ''OCT2'' or ''organic cation transporter-2'') is a protein that in humans is encoded by the ''SLC22A2'' gene. Poly specific organic cation transporters in the liver, kidney, intestine, and other orga ...

, and uridine diphosphate-glucuronosyltransferases, each of which remove drugs from circulation; isavuconazonium will increase the amount of drugs that are affected by those proteins and may increase their toxicities.

Pharmacology

After oral or intravenous administration, isavuconazonium is rapidly hydrolysed by

esterase In biochemistry, an esterase is a class of enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis (and as such, it is a type of hydrolase). A wide range of different esterases exist that differ ...

s in blood or the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

to the active form, isavuconazole. Isavuconazole works by

inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...

lanosterol 14α-demethylase Lanosterol 14α-demethylase (CYP51A1) is the animal version of Sterol 14-demethylase, a cytochrome P450 enzyme that is involved in the conversion of lanosterol to 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol. The cytochrome P450 isoenzymes are ...

, the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

responsible for converting

lanosterol Lanosterol is a tetracyclic triterpenoid and is the compound from which all animal and fungal steroids are derived. By contrast, plant steroids are produced via cycloartenol. In the eyes of vertebrates, lanosterol is a natural constituent, havin ...

ergosterol Ergosterol (ergosta-5,7,22-trien-3β-ol) is a mycosterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells. Because many fungi and protozoa cannot survive without ergostero ...

via a

demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen at ...

reaction. The resulting depletion of ergosterol and buildup of lanosterol compromise the fungal

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. Mammalian

is more resistant to inhibition by

azole Azoles are a class of five-membered heterocyclic compounds containing a nitrogen atom and at least one other non-carbon atom (i.e. nitrogen, sulfur, or oxygen) as part of the ring. Their names originate from the Hantzsch–Widman nomenclature. Th ...

s, making the drug's effects mostly specific to fungi.

Chemistry

Isavuconazonium comprises an ''N''-(3-acetoxypropyl)-''N''-methylamino-carboxymethyl group linked through an ester moiety to the triazole nitrogen in isavuconazole. In the aquatic media of the body, the isavuconazole molecule is transformed into monohydrate.

History

Isavuconazole and isavuconazonium were discovered in Japan by researchers at

Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Switzerland, Swiss multinational corporation, multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, ...

's research center in

Kamakura , officially , is a city of Kanagawa Prefecture in Japan. It is located in the Kanto region on the island of Honshu. The city has an estimated population of 172,929 (1 September 2020) and a population density of 4,359 people per km2 over the tota ...

. Basilea Pharmaceutica, which had been spun out of Roche to develop antimicrobial assets, developed isavuconazonium through Phase II clinical trials. In February 2010, Basilea partnered with

Astellas Pharma is a Japanese multinational pharmaceutical company, formed on 1 April 2005 from the merger of and . Astellas is a member of the Mitsubishi UFJ Financial Group (MUFJ) keiretsu. History Early foundations Fujisawa Shoten was started in 1894 ...

to complete Phase III trials, obtain regulatory approvals, and market the drug. In 2013 and 2014, the partners won

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designation in the US for isavuconazonium for treating invasive aspergillosis, mucormycosis, and invasive candidiasis. In 2014, Basilea and Astellas amended the agreement to give Astellas sole marketing authority in North America, and Basilea the rights to market in the rest of the world. The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) granted approval in March 2015, and the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

(EMA) approved it in October 2015. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. In 2017, Basilea licensed rights to Pfizer to market isavuconazole in Europe and other regions.

References

{{Authority control Astellas Pharma CYP3A4 inhibitors Fluoroarenes Lanosterol 14α-demethylase inhibitors Nitriles Phenylethanolamines Prodrugs Tertiary alcohols Thiazoles Triazole antifungals Quaternary ammonium compounds Disubstituted pyridines