Bosutinib

Uses

Bosutinib is an antineoplastic agent used for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adults with inadequate clinical response to other treatments.

Treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy in adult patients.

Bosutinib is also used to associated treatment for these conditions: Refractory, accelerated phase Chronic myelogenous leukemia, Refractory, blast phase Chronic myelogenous leukemia, Refractory, chronic phase Chronic myelogenous leukemia

How Bosutinib works

Bosutinib is a tyrosine kinase inhibitor. Although it is able to inhibit several tyrosine kinases such as Src, Lyn, and Hck, which are members of the Src-family of kinases, its primary target is the Bcr-Abl kinase. The Bcr-Abl gene is a chimeric oncogene created from the fusion of the breakpoint-cluster (Bcr) gene and Abelson (Abl) tyrosine gene. This chromosomal abnormality results in the formation of what is commonly known as the Philadelphia chromosome or Philadelphia translocation. The Bcr-Abl gene expresses a particular kinase that promotes the progression of CML. A decrease in the growth and size of the CML tumour has been observed following administration of bosutinib. Bosutinib did not inhibit the T315I and V299L mutant cells.

Toxicity

Most common adverse reactions (incidence greater than 20%) are diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, and fatigue. Because bosutinib is not an inhibitor of c-KIT or PDGF receptor, it has less hematologic toxicities.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of bosutinib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of bosutinib.
• Take with food. Coadministration with a high-fat meal may increase the AUC of bosutinib.

[Moderate] ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of bosutinib.

When given with a high-fat meal, bosutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.8- and 1.7-fold, respectively.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of bosutinib, which is primarily metabolized by CYP450 3A4.

However, the interaction has not been studied.

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

MANAGEMENT: Bosutinib should be administered with a meal.

The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided.

Bosutinib Drug Interaction

Moderate: fluticasone / vilanterolUnknown: charcoal, fexofenadine, cetirizine, zolpidem, diphenhydramine, ethinyl estradiol / norethindrone, arginine, levocarnitine, cysteine, lithium, metoprolol, oxycodone, valproic acid, thiamine, cyanocobalamin, pyridoxine, cholecalciferol, phytonadione, menaquinone

Bosutinib Disease Interaction

Moderate: cardiovascular disease, fluid retention, bone marrow suppression, dehydration, liver disease, renal impairment

Volume of Distribution

Apparent volume of distribution = 6080 ± 1230 L.

Elimination Route

Food increase the exposure of bosutinib. Tmax, single dose, cancer patients, fed-state = 4-6 hours; After 15 daily doses of bosutinib 500 mg with food in CML patients, the pharmacokinetic parameters are as follows: Cmax = 200 ng/mL; AUC = 3650 ng∙h/mL

Half Life

Terminal phase elimination half-life, single oral dose, fed-state = 22.5 hours

Clearance

Mean clearance (CL/F), single oral dose, fed-state = 189 L/h

Elimination Route

When given a single oral dose, 91.3% of the dose was recovered in feces and 3% of the dose recovered in urine.

Innovators Monograph

You find simplified version here Bosutinib