Fedratinib

Uses

Fedratinib is indicated to treat adults with primary or secondary myelofibrosis that is either intermediate-2 or high risk.

Fedratinib is also used to associated treatment for these conditions: Primary Myelofibrosis, Secondary Myelofibrosis

How Fedratinib works

Fedratinib is an inhibitor of Janus Activated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3. JAK2 is highly active in myeloproliferative neoplasms like myelofibrosis. Fedratinib's inhibition of JAK2 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5, which prevents cell division and induces apoptosis.

Toxicity

Data regarding fedratinib in overdose is not readily available. Patients given 680mg/day experienced a greater incidence and severity of adverse effects including anemia, thrombocytopenia, gastrointestinal toxicity, hepatic toxicity, and elevated amylase and lipase. These effects were treated symptomatically as well as by reducing the dose or temporarily stopping fedratinib.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of fedratinib. Dose reduction may be necessary.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of fedratinib and may reduce its serum concentration.
• Take with or without food. Food may help reduce adverse effects of fedratinib such as nausea and vomiting.

[Moderate] MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4.

Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

Orange juice is not expected to interact with these drugs.

Fedratinib Drug Interaction

Moderate: prednisolone ophthalmic, pantoprazoleUnknown: bumetanide, deferoxamine, bisacodyl, aluminum hydroxide / magnesium hydroxide / simethicone, multivitamin with minerals, bromfenac ophthalmic, denosumab

Fedratinib Disease Interaction

Major: severe hepatic impairment, thiamine deficiency, cardiovascular risk, malignancy, thrombosisModerate: renal impairment

Volume of Distribution

The apparent volume of distribution is 1770L.

Elimination Route

A 400mg oral dose results in a C_max of 1804ng/mL and an AUC of 26,870ng/*hr/mL. Fedratinib has a T_max of 1.75-3 hours. A high fat breakfast does not significantly affect the absorption of fedratinib.

Half Life

The half life of fedratinib is 41 hours with a terminal half life of 114 hours.

Clearance

The clearance of fedratinib is 13L/h.

Elimination Route

An oral dose of fedratinib is 77% eliminated in the feces with 23% as unchanged drug. 5% is eliminated in the urine, with 3% as unchanged drug.

Innovators Monograph

You find simplified version here Fedratinib