Bosutinib Breakthrough: A New Hope for Chronic Myelogenous Leukemia

Overview:

Tyrosine kinase inhibitors (TKIs) such as Bosutinib are used to treat leukemia (chronic myeloid leukemia) and other cancer conditions. It is a member of the BCR-ABL tyrosine kinase inhibitor medication class, which targets abnormal proteins that support the development of cancer cells. Bosutinib was approved by the US (United States) FDA (Food and Drug Administration) in December 2017.

Indications:

Bosutinib is a medication used to treat adult patients with chronic myelogenous leukemia (CML), a particular kind of leukemia. It is applied when the patient's illness is chronic, rapid, or in a blast phase, and prior treatments are either intolerable or poorly tolerated.

Contraindications:

Bosutinib, which is used in some clinical trials, may cause allergies or hypersensitivity reactions in certain persons. It is essential, nevertheless, that just over 0.2 percent of individuals receiving Bosutinib throughout those studies experienced this hypersensitive reaction, which resulted in a severe allergic response known as anaphylactic shock.

Dosage Forms and Available Strengths: The pills are available in the form of 100 milligrams (mg) and 500 mg tablets. Both have an oval form, are smooth, and have a thin layer covering them.

For Patients

What Is Chronic Myelogenous Leukemia?

Chronic Myeloid Leukemia (CML), also referred to as chronic myelogenous leukemia, is a kind of cancer that starts in particular bone marrow blood cells. Early myeloid cells in CML undergo a genetic alteration that results in the abnormal gene BCR-ABL. This change converts the cell to a CML cell, which causes leukemia cells to develop and accumulate uncontrollably in the bone marrow and bloodstream. There is a chance that these cells can move to other organs, such as the spleen. Even while CML usually advances slowly, it can suddenly develop into an acute leukemia that grows quickly and is difficult to cure. Despite being more common in adults, CML can sometimes affect youngsters and is treated similarly to adult patients.

What Are the Clinical Uses of Bosutinib?

Bosutinib is a medication used to treat Chronic Myeloid Leukemia (CML), a kind of cancer that mostly affects white blood cells. Adults who have just been diagnosed with CML or those who do not respond well to other drugs because of side effects or ineffectiveness use it. Bosutinib is a member of the class of drugs known as kinase inhibitors. Its function is to prevent a troublesome protein from directing cancer cells to proliferate and develop. Bosutinib aids in stopping the cancer cells from proliferating in this way.

How Should Bosutinib Be Used?

Oral tablets containing Bosutinib are available. It is typically taken once daily with food. Take Bosutinib daily at approximately the same time as prescribed. Take it only as frequently as the doctor prescribes. Avoid breaking, chewing, or crushing the tablets; swallow them whole. Avoid touching any of the broken or crushed tablets with bare hands. Depending on the patient's response to the medication and any side effects, the doctor may modify the patient's dose of Bosutinib or temporarily or permanently stop the treatment. Throughout treatment, the patient should discuss their opinions with the doctor. Even if the patient feels well, they should still take Bosutinib and should not stop taking it without first consulting their physician.

What Is the Prescribed Dosage and Method of Administration For Bosutinib?

• Recommended Dosage:

  • Follow the directions given by the physician and take Bosutinib.

  • One 500 mg (milligrams) daily dose with food is the standard.

  • Take it as long as the patient can tolerate it or until the problem worsens.

  • If a dosage is missed by more than 12 hours, the patient should skip the missed dose and take the prescribed amount the next day.

• Escalation of Dose:

  • Should the patient's blood reaction still be incomplete by week eight, the physician might up the dosage to 600 mg once daily.

  • This is for people who are currently taking 500 mg daily and are not experiencing any serious adverse effects.

• Modifying the Dose to Address Side Effects:

  • The medication may be stopped until the patient's liver enzyme levels return to normal and then resumed at a reduced dosage if necessary.

  • The medication may be stopped for severe diarrhea until symptoms improve and then continued at a reduced dosage.

  • If there are any other serious adverse effects, the medication may be stopped until the problem is fixed. At this point, it may be restarted at a reduced dose if necessary.

What Are the Side Effects of Bosutinib?

Bosutinib may cause adverse reactions. Give the doctor a call if a person has any of the following symptoms:

• Urine that is tea- or dark-colored.

• Variations in the quantity or frequency of urine.

• Lightheadedness.

• Chest ache.

• Weakness or fatigue.

• Breathing difficulties and coughing.

• Unexpected bruises or bleeding.

• Skin and eyes are turning yellow.

• Nausea.

• Decrease in appetite.

• Vomiting.

• Chills, fever, sore throat, or infection-related symptoms.

• Abrupt abdominal pain.

• Blood in the feces or urine.

• Ear ringing.

• Face, hands, ankles, feet, or legs swelling.

• Breathing or swallowing difficulties.

• Hives.

• Rash.

• Itchiness.

• Alteration in the sense of taste for food.

• Headache.

• Unexpected weight increase.

What Are the Things to Inform the Doctor Before Taking Bosutinib?

• Allergies: Patients should notify their medical team of any allergies to Bosutinib or any of the tablet's ingredients. It is best if they ask their pharmacist for an ingredient list.

• Overview of Medication: Give a thorough inventory of all prescription and over-the-counter drugs, vitamins, supplements, and herbal remedies. Namely, list the following:

  • Antifungals such as Itraconazole and Ketoconazole.

  • Antiretroviral drugs (Saquinavir, Ritonavir, Nelfinavir, and Indinavir).

  • Medicines that reduce acid reflux (such as Pantoprazole, Rabeprazole, Lansoprazole, and Omeprazole).

  • Others based on their past prescription history.

• Medication For the Stomach: If a person takes antacids or medications that lower stomach acid (like Cimetidine, Famotidine, or Ranitidine), they should take them two hours before or following Bosutinib.

• Herbal Products: Any herbal products they use, particularly St. John's wort, should be disclosed.

• Medical History: People should disclose all past medical issues, including high blood pressure, diabetes, and ailments affecting the kidneys, liver, or heart.

• Pregnancy and Birth Control: A pre-treatment pregnancy test is necessary if they are or plan to get pregnant. Effective birth control is crucial both during and for two weeks following the final dose of Bosutinib treatment. If they become pregnant, they should get in touch with their doctor right away because Bosutinib can harm the developing fetus.

• Nursing: During the two weeks following the last dosage of Bosutinib, individuals should refrain from nursing.

• Fertility Considerations: They should talk to their doctor about possible effects on fertility in both men and women.

Dietary Considerations: One should avoid grapefruits and grapefruit-related goods while using Bosutinib. Patients should also avoid using any supplements that include grapefruit extract.

Missed Dose: One should consume medication as soon as possible after forgetting to take it. They should, however, forego the missed dose and resume their regular dosing plan if more than 12 hours passed since their last dose. It is inappropriate for them to take two doses to make up for what they missed.

Overdose: Contact emergency services at once if the person has passed out, experienced a seizure, is having difficulty breathing, or refuses to wake up.

Storage: Keep this medication tightly closed, out of children's reach, and in the original container. Store it at room temperature, out of the bathroom, and away from intense heat or moisture sources. Prescription drugs must be kept out of children's eyes and reach. Specific containers, such as eye drops, creams, patches, inhalers, or weekly pill minders, may not be child-resistant and can be readily opened by small children. Always secure safety caps to prevent poisoning, and store medications right away in a safe place that is high and out of their reach.

Disposal: Make sure that unwanted prescriptions are disposed of in a way that keeps pets, kids, and other people from consuming them. But avoid flushing this drug down the sink. A pharmaceutical take-back program is the most effective way to eliminate it.

For Doctors

Pharmacodynamics:

Clinical trials showed that the efficacy of the medication Bosutinib rose with increasing drug exposure, suggesting a connection between drug concentrations and therapeutic response. On the other hand, a similar correlation was found for safety events, with higher drug exposure being linked to a higher chance of such occurrences. In terms of cardiac electrophysiology, combining the potent CYP3A inhibitor ketoconazole with a single oral dosage of 500 mg of Bosutinib did not result in any clinically significant prolongation of the QT interval, indicating that Bosutinib did not negatively impact the electrical activity of the heart in these circumstances.

Mechanism of Action:

Bosutinib inhibits tyrosine kinase, specifically Bcr-Abl kinase, which is responsible for promoting CML leukemia. Additionally, it inhibits other essential proteins in the proliferation of cancer cells, such as Src, Lyn, and Hck. Bosutinib was useful in mouse trials in decreasing CML tumors and lowering the growth of myeloid tumors that had developed resistance to Imatinib, a different medication. It did not, however, work on cells that had specific mutations. In short, since it inhibits the action of critical proteins essential for the proliferation of cancer cells, Bosutinib is a promising treatment for some forms of leukemia, especially when other medications are less successful.

Pharmacokinetics:

• Absorption: The body reaches its maximum concentration of Bosutinib (500 mg) in four to six hours when cancer patients take a single dose of the medication with food. The body's Bosutinib concentration rises in direct proportion to the dosage. The maximum concentration of Bosutinib was 200 ng/mL (nanograms per milliliter) after 15 daily doses with food, while the body's total Bosutinib concentration over time was 3650 ng/mL. The concentration and total amount of Bosutinib in the body rise by 1.8 and 1.7 times when taken with a high-fat meal.

• Distribution: Bosutinib is dispersed throughout the body with an apparent volume of 6080 L (liters) following a single dosage of 500 mg taken with food. Blood proteins are highly bound by Bosutinib (94 to 96 percent).

• Metabolism: The liver enzyme CYP3A4 is primarily responsible for the breakdown of Bosutinib. N-demethylated bosutinib (M5) and oxydechlorinated bosutinib (M2) are the main by-products detected in blood, yet they are inert.

• Elimination: When cancer patients take 500 mg of Bosutinib with meals, it takes the body roughly 22.5 hours to excrete half of the medication. The average clearing rate is 189 L/h (liters per hour). In research using radiolabeled Bosutinib in healthy male subjects, feces contained 91.3 percent of the dose, whereas urine contained three percent.

• Hepatic Impairment: In a study involving individuals with liver issues, the concentration of Bosutinib rose in those with mild impairment (2.4 times), moderate impairment (two times), and severe impairment (1.5 times). In these groups, there was a corresponding increase in total body Bosutinib of 2.3, 2, and 1.9 fold.

Drug Interactions:

• CYP3A Inhibitors: These chemicals can dramatically raise the body's concentration of the Bosutinib drug when combined with other medications. Ketoconazole was employed in this particular trial, and it raised Bosutinib levels by approximately 5.2 times for Cmax (highest concentration) and 8.6 times for AUC (total exposure).

• CYP3A Inducers: On the other side, when combined, drugs such as Rifampin can lower the concentration of Bosutinib. Rifampin reduced the Cmax and AUC in this experiment by 86 percent and 94 percent, respectively.

• P-Gp Substrates: Bosutinib may raise the concentrations of medications carried by the P-glycoprotein (P-gp) protein. According to the study, Bosutinib may increase the concentration of these medications.

• Ph-Altering Medications: The environment's pH (potential of hydrogen) can affect Bosutinib’s water solubility. The pH-altering drug Lansoprazole reduced the Bosutinib Cmax by 46 percent and the AUC by 26 percent in this trial.

Clinical Studies: To assess the safety and efficacy of Bosutinib, a 500 mg once-daily treatment for Chronic Myeloid Leukemia (CML), a clinical trial comprising 546 patients in various stages of the disease was carried out. Imatinib intolerance denoted the inability to tolerate Imatinib because of toxicity, whereas insufficient response or problems with tolerance characterized Imatinib resistance. According to the findings, 27 percent of patients were intolerant, and 73 percent were resistant to Imatinib. At 24 weeks, 33.8 percent of chronic phase CML patients who had previously received just Imatinib treatment demonstrated a significant cytogenetic response (MCyR), compared to 26.9 percent of individuals who had received both Imatinib and other tyrosine kinase inhibitors. The trial results showed that response rates and duration of Bosutinib treatment varied between CML phases, suggesting that the treatment may effectively control CML intolerance or resistant to Imatinib. However, individual responses may vary.

Warnings and Precautions:

• Gastrointestinal Problems: Some users of Bosutinib may have digestive problems, such as diarrhea, abdominal pain, nausea, and vomiting. Physicians should monitor these symptoms and treat them with fluids or medication. According to a study, most diarrhea cases began after two days of therapy and persisted for around a day. If these problems get worse, the treatment can be changed or discontinued.

• Blood-Related Problems: Bosutinib can also have an impact on blood cells, which can result in diseases including thrombocytopenia, neutropenia, and anemia, which low platelet, white blood cell counts, and red blood cells respectively characterize. People receiving this therapy should get blood tests regularly to check these levels. The course of treatment may be changed or discontinued if problems arise.

• Liver Issues: Bosutinib may occasionally result in liver issues. Doctors will routinely check liver enzyme levels, particularly during the first several months of treatment. The course of treatment may need to be changed or discontinued if liver problems are detected. A very tiny percentage of individuals experienced significant liver problems, but upon stopping the medication, they recovered.

• Fluid Retention: Bosutinib may cause the body to retain fluid in different areas. This may involve edema surrounding the lungs or heart. A tiny percentage of individuals in research had severe fluid retention. Using conventional procedures, doctors will monitor and manage this; if needed, they may modify or cease the treatment.

• Pregnancy Risks: Not enough research has substantiated Bosutinib’s safety during pregnancy. However, research on animals has demonstrated that it is harmful to the growing fetus. When using Bosutinib, fertile women should take steps to prevent getting pregnant, and if they do, they should be informed of the possible risks to the unborn child.

Use in Specific Populations:

• Conception: One medicine, Bosutinib, is classified as potentially harmful to the fetus in pregnancy. When used by expectant mothers, it may have adverse effects on the fetus. Individuals who become pregnant or who use Bosutinib while pregnant should be made aware of the potential dangers to the developing fetus. Fetal abnormalities such as fused sternebrae (the condition where the bones (sternebrae) in the breastbone (sternum) are joined or fused) and a slight decrease in fetal body weight were observed at high doses in rabbit investigations. Compared to people taking a regular dose of Bosutinib, the dose administered to rabbits resulted in exposures four times higher.

• Mothers Who Are Nursing: Whether Bosutinib enters human milk is unknown. Studies on rats revealed that Bosutinib and its metabolites were present in milk and that radioactivity was discovered in the plasma of nursing rat pups whose moms had taken Bosutinib. Mothers must weigh the hazards to their nursing infants against the benefits of continuing Bosutinib when deciding whether to quit nursing.

• Use in Pediatrics: Bosutinib’s efficacy and safety in people under eighteen are unknown.

• Use in the Older People: In a clinical investigation, there were no apparent variations in safety or effectiveness between younger and older individuals (65 years of age and above). Although there have not been any notable variations seen in reported experiences, caution is suggested because some older adults may be more sensitive.

• Impairment of the Liver: Individuals with liver problems should take 200 mg daily. Bosutinib exposure was higher in patients with hepatic impairment than in healthy individuals in a trial.

• Renal Impairment: According to the analysis, Bosutinib exposure in the investigated range (25 mL/min to 120 mL/min - milliliters per minute) is not significantly impacted by kidney function (creatinine clearance).