Overview

The medication Quizartinib targets a protein called FLT3, which is frequently present in acute myeloid leukemia (AML), a kind of aggressive blood cancer. Many cases of this malignancy have a mutation in FLT3, called FLT3-ITD, which worsens the prognosis for patients. By inhibiting FLT3, especially the mutant form, Quizartinib helps increase the survival rates of AML patients. Studies on patients whose cancer has returned or has not responded to previous treatments have shown that it is effective in treating these patients. To ensure that it is used safely, more research is necessary as it can also have major side effects, such as QT prolongation. The United States Food and Drug Administration (US-FDA) approved Quizartinib on July 20, 2023.

Drug Group:

Quizartinib is a member of the class of drugs known as kinase inhibitors. It works by blocking a particular natural chemical that cancer cells may need to proliferate and flourish.

Indications:

During the first treatment phase (induction), Quizartinib is a drug that is used in conjunction with regular Cytarabine and Anthracycline medications. During the second treatment phase (consolidation), Quizartinib is also used in conjunction with Cytarabine. Additionally, it is utilized as a stand-alone maintenance treatment following consolidation chemotherapy. This treatment plan is intended for adults who have just received a diagnosis of acute myeloid leukemia (AML), a kind of blood cancer. It pertains specifically to individuals whose AML has the FLT3 internal tandem duplication (ITD) genetic marker, which an FDA-approved test can find.

Contraindications:

Patients with extremely low potassium or magnesium levels, a condition known as severe hypokalemia (low potassium level in blood), or severe hypomagnesemia (low magnesium level in blood) should not take Quizartinib. Additionally, it is not advised for those with prolonged QT syndrome or those who have already experienced significant cardiac rhythm issues such as torsades de pointes or ventricular arrhythmias (abnormal cardiac rhythms that may result in potentially harmful heartbeat abnormalities).

Dosage Forms and Available Strengths

These tablets are prescription drugs. One variety contains 17.7 mg (milligrams) of Quizartinib. It is spherical, white, and has a thin layer covering it. It is marked with "DSC511" on one side.

The same material is present in 26.5 milligrams in the other form. It is spherical, golden, and covered, and "DSC512" is written on this one.

For Patients:

What Is FLT3-ITD Positive Acute Myeloid Leukemia?

An acute myeloid leukemia (AML) with a FLT3 internal tandem duplication (FLT3-ITD) mutation is a blood cancer that grows quickly and usually has a poor prognosis. Although remission is frequently achieved with aggressive chemotherapy, the condition frequently returns.

What Are the Clinical Uses of Quizartinib?

Quizartinib is a medicine used to treat acute myeloid leukemia (AML), a particular kind of cancer, in conjunction with other chemotherapy medications. A malignancy that targets white blood cells is called AML. Quizartinib is a member of the class of drugs known as kinase inhibitors. It functions by blocking an endogenous chemical that may facilitate the growth and multiplication of cancerous cells.

How Should Quizartinib Be Used?

Quizartinib is available as an oral tablet. It is typically taken once a day, with or without food. Quizartinib dosage will be determined by the doctor. Take Quizartinib daily at approximately the same time. Pay close attention to the instructions on the prescription label, and ask the pharmacist or doctor to clarify any parts one is unsure about. Follow the directions properly when taking Quizartinib. Never take more or less of it, or take it more frequently than the doctor has instructed. One should not split, chew, or crush the tablets; instead, swallow them whole.

The doctor would likely monitor for QT prolongation with an ECG (electrocardiogram) test before starting on a low dose of Quizartinib and progressively increasing it.

What Are the Side Effects of Quizartinib?

Quizartinib may cause adverse reactions. If any of these symptoms annoy the patient or do not go away, let the doctor know:

Itchy or irritated eyes.
Nosebleeds.
Diarrhea.
Vomiting or feeling ill in the stomach.
Mouth sores or ulcers.
Inability to fall asleep.
Headache.
Reduced appetite.

Certain adverse effects may be dangerous.

Feeling disoriented or confused.
Coughing.
Fever.
Rapid or difficult breathing.
Exhaustion.

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

Allergies: If one has any allergies to Quizartinib, other drugs, or any of the substances in the tablets, let the doctor and pharmacist know before taking the prescription. For an ingredient list, consult the medication guide or ask the pharmacist.
Medication Interactions: Let the doctor and pharmacist know about all the vitamins, nutritional supplements, herbal items, and prescription and over-the-counter medications one is currently taking or intends to use while taking Quizartinib. The doctor might need to carefully monitor for any negative effects or adjust the dosages of the medications.
Pregnancy and Contraception: Quizartinib use during pregnancy carries a risk of damage to the developing fetus. If one becomes pregnant while taking Quizartinib, get in touch with the doctor right away. Pregnancy tests may be necessary for females before commencing Quizartinib. Effective contraception should be used by females both during and after therapy. While on Quizartinib and for a while after stopping the medication, males may also need to utilize effective contraception with their female partners. Avoid breastfeeding for one month after quitting Quizartinib and while taking it.
Surgery: Notify the doctor or dentist that one is taking Quizartinib if the patient is having surgery, including dental surgery.

Dietary Consideration: Stick to the regular diet unless the doctor says otherwise.

Storage: Keep this medication, Quizartinib out of children's reach and in the sealed container it came in. Keep it out of the bathroom and at room temperature, away from sources of heat and moisture. Since many pharmaceutical containers are not child-resistant and are easily opened by small children, it is crucial to keep all medications out of children's sight and access. Always lock safety caps and keep drugs in a secure place up high and out of children's reach to avoid accidental poisoning.

Disposal: It is important to appropriately dispose of any unneeded medications to avoid pet or child ingestion. This drug should not be flushed down the toilet. By using a pharmaceutical take-back service, one may get rid of the medication in the best way possible. To learn more about take-back initiatives in the area, speak with the pharmacist or contact the recycling and trash department.

Missed Dose: Take the missed Quizartinib dose as soon as one recalls it. On the other hand, if the next dose is almost here, skip the one that is missed and stick to the usual dosage plan. Never take two doses to make up for one that is missed. If the patient has vomiting after taking Quizartinib, skip the following dose and stick to the prescribed schedule.

Overdose: Make sure to contact the poison control helpline if someone takes too much of this medication. Make an immediate call to emergency services if the person passes out, has a seizure, has difficulty breathing, or is unable to awaken.

For Doctors

Pharmacodynamics: The complete characterization of the exposure-response connection and the time course of the pharmacodynamic response is necessary to ensure the safety and efficacy of Quizartinib. Lab investigations on cardiac electrophysiology show that Quizartinib mostly blocks a particular potassium current. Higher Quizartinib concentrations may, with some degree of uncertainty, cause the QTcF interval, a gauge of cardiac rhythm, to extend by 18 to 24 milliseconds. During ongoing treatment, this prediction was made at particular doses.

Mechanism of Action: A small drug called Quizartinib prevents the body's FLT3 protein from functioning as it should. Similar to a switch, FLT3 instructs cells to proliferate and divide. However, FLT3 is overactive in certain illnesses, such as some forms of leukemia, which leads to uncontrollably fast cell growth. Quizartinib functions by binding to FLT3 and inhibiting its function. This helps to slow down the disease by preventing the cells from developing too quickly. Quizaratinib was able to reduce the size of the tumors in mice tested for leukemia, which depends on FLT3 being overactive.

Pharmacokinetics:

It is still unclear how Quizartinib interacts with the body and how it affects cancer patients.

Absorption: When taken orally, Quizartinib is efficiently absorbed four hours after ingesting. It is usually seen when the blood level reaches its peak. About five to six hours after taking Quizartinib, its active form (AC886) reaches its peak.
Efficacy: Within a specific dose range, Quizartinib exhibited an increase in efficacy in individuals diagnosed with acute myeloid leukemia (AML). This indicates that higher blood levels of Quizartinib were caused by larger dosages.
Distribution: Quizartinib is primarily found in the bloodstream, but it can travel throughout the body. It has a considerable binding affinity for blood proteins.
Metabolism and Elimination: The body mostly breaks down Quizartinib through the action of CYP3A4 or 5 enzymes. The same enzymes that produce and break down AC886 also tear it down. Only a small amount of Quizartinib is excreted from the body in the urine after a dose; the majority is eliminated through the feces.
Specific Populations: There are no appreciable differences in Quizartinib blood levels according to age, sex, race, or body weight. Compared to those with normal kidney or liver function, Quizartinib did not substantially change the bodies of people with mild to moderate renal or liver diseases. The effects on people with severe liver or kidney problems are still unknown, though.

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

Choosing a Patient: Patients are selected for Quizartinib treatment for AML depending on whether or not they have the FLT3-ITD mutation, which is identified by FDA-approved assays.
Suggested Dosage:
- Quizartinib with induction Cytarabine and Anthracycline for a total of two cycles, high-dose Cytarabine for a maximum of four cycles, and maintenance therapy for up to 36 cycles are all part of the treatment. The course of the disease, its toxicity, or the conclusion of the cycle dictate how long the treatment will last.
- The dosage of Quizartinib changes based on the stage of treatment and the QTcF measurement of the patient's heart. It is given orally once daily, with modifications as needed.
- Avoid taking additional doses of Quizartinib if one misses it or throws up. Take it as soon as feasible that same day, or the following day, and go back to the routine.
Checking for Side Effects and Modifying Dosage:
- Start Quizartinib only when the patient's QTcF falls within a safe range.
- To evaluate heart health throughout treatment, routine ECGs are required.
- Treat electrolyte abnormalities and stay away from medications that lengthen the QT interval.
- Modify Quizartinib dosage as per the severity of adverse effects, such as QT prolongation, irregular cardiac rhythms, or low levels of magnesium or potassium in the blood.
Adjusting the Dosage of Potent cyp3a Inhibitors:
- Quizartinib dosage needs to be lowered if it is taken with potent CYP3A inhibitors. Once the CYP3A inhibitor has been stopped, wait for a predetermined amount of time before starting Quizartinib again at the original dose.

Drug Interactions:

Strong CYP3A Inhibitors: When Quizartinib is used with some pharmaceuticals that potently block the CYP3A enzyme, which is in charge of breaking down drugs within the body, the circulation may contain higher concentrations of Quizartinib. This increased exposure could make it more likely that Quizartinib-related side effects will manifest. Physicians may choose to lower the dosage of Quizartinib when it is given in conjunction with strong CYP3A inhibitors to lessen this risk.
Strong or Moderate CYP3A Inducers: On the other hand, systemic exposure to Quizartinib may be reduced when used with medications that cause CYP3A activity. This could result in the medication not staying in the body as long as planned, which could reduce its therapeutic efficacy. It is usually not recommended to administer Quizartinib concurrently with strong or moderate CYP3A inducers to preserve its efficiency.
QT Interval Prolonging Drugs: VANFLYTA can extend the QT interval, a particular cardiac activity assessment. There is an increased risk of additional lengthening of the QT interval when using this medication in combination with other drugs that also cause this effect. People may be more susceptible to a certain kind of arrhythmia due to this. It is advised that individuals taking Quizartinib, in addition to medications that are known to lengthen the QT interval, have more regular electrocardiograms (ECGs) to reduce this risk. Certain antifungal agents, anti-nausea medications such as Ondansetron, and other drugs can prolong the QT interval.

Clinical Studies: In clinical trials, Quizartinib was examined in combination with chemotherapy in a QuANTUM-First trial that included 539 newly diagnosed AML patients with a particular genetic mutation known as FLT3-ITD. In addition to chemotherapy, patients received either Quizartinib or a placebo for induction, consolidation, and maintenance therapy. In comparison to a placebo, Quizartinib was found to improve overall survival in the research. The survival rate was much higher for patients who got Quizartinib. More improvement in survival was also seen in patients who got Quizartinib during maintenance therapy following chemotherapy. Similar to the placebo, Quizartinib likewise produced a complete remission rate, although the remission lasted longer. These findings suggest that Quizartinib can effectively treat newly diagnosed AML patients with FLT3-ITD mutations and increase their chances of survival when combined with chemotherapy.

Warnings and Precautions:

Recognition of Cardiac Risks and QT Prolongation: When taken in larger dosages, the medicine Quizartinib, which is used to treat some types of leukemia, might cause the heart's QT interval to be prolonged, increasing the risk of cardiac rhythm issues. In contrast to many other medications, Quizartinib modifies the QT interval of the heart by blocking a particular potassium channel. Studies involving patients with Acute Myeloid Leukemia (AML) and FLT3-ITD-positive AML have shown that this might result in major heart rhythm problems such as ventricular fibrillation, Torsades de Pointes, cardiac arrest, and in certain circumstances, sudden death. Most of these occurrences happened in the early stages of treatment.
Safety Precautions and Advice: Patients with certain cardiac disorders or risk factors for heart rhythm issues, such as those with uncontrolled high blood pressure, recent heart attacks, or serious heart illness, must not take Quizartinib. Physicians should assess the patient's QT interval and address any electrolyte imbalances before initiating Quizartinib. Regular ECG (heart rhythm test) monitoring is required during treatment to check for changes in the QT interval. Quizartinib may need to be taken at a different dose or stopped entirely if the QT interval lengthens too much. When Quizartinib is taken with other drugs that are known to influence the QT interval, extra care and observation are required. Furthermore, because of its significant cardiac risks, Quizartinib can only be obtained through a specific program (REMS), which requires patient counseling and certification from physicians and pharmacies.
Fetal Health Concerns: If taken while pregnant, Quizartinib can cause harm to the fetus because tests on animals exposed to the drug found problems in the progeny. As a result, women who are pregnant should not take Quizartinib, and women who are of reproductive age should use reliable contraception both during and after quitting Quizartinib. The male partners should also follow the same caution.

Non-clinical Toxicology: Studies on Quizartinib's carcinogenicity, or the possibility that it could cause cancer, have not been carried out. Quizaratinib's potential to induce genetic mutations was tested in lab settings; it was mutagenic in a bacterial test but not in a rat test. Furthermore, in rat studies conducted in vivo and other in vitro, Quizartinib did not result in genetic harm. Although research on animal fertility has not been done, repeated Quizartinib doses in rats and monkeys caused negative effects on their reproductive systems. At doses of 0.2 and 0.4 times the maximum recommended human dose, respectively, male mice developed problems with testicular damage and sperm production, while female animals exhibited problems such as ovarian cysts and vaginal abnormalities. Nevertheless, once the animals stopped receiving Quizartinib for around a month, the majority of these changes were reversible.

Use in Specific Populations:

Pregnancy: It has been discovered that pregnant women who take the medicine Quizartinib, which is prescribed for specific circumstances, may pose a risk to their unborn children. This finding is supported by research on animals as well as knowledge of how the drug functions within the body. Although research on pregnant women using Quizartinib has not been done precisely, tests on pregnant rats have revealed that the drug has negative effects on the growing fetus. When considering the use of Quizartinib, healthcare providers should advise pregnant women about these possible dangers to their unborn children. Furthermore, it is claimed that although the general US population typically has a two to four percent chance of birth abnormalities, miscarriages occur in 15 to 20 percent of clinically confirmed pregnancies.
Lactation: Regarding Quizartinib or its byproducts' presence in breast milk and its effects on nursing infants, there is a lack of knowledge. Women taking Quizartinib for therapy are advised not to breastfeed for one month following the final dosage because of the potential for serious adverse effects on the unborn child.
Reproductive Potential of Males and Females: It is important to think about the possible pregnancy risks linked with using Quizartinib for both men and women of reproductive age. It is advised to ascertain whether female patients are pregnant before beginning Quizartinib medication. Patients who are female and capable of getting pregnant should take effective contraception for seven months after Quizartinib therapy is stopped. Likewise, male patients who have partners who may become pregnant must utilize reliable contraception both during treatment and for four months after Quizartinib therapy is stopped. It is important to note that Quizartinib has a transient, reversible effect on fertility in both men and women.
Pediatric Use: Quizartinib’s suitability for children has not been demonstrated since not enough testing has been done to evaluate its safety and effectiveness in pediatric patients.
Use in Elderly: A small proportion of older persons 65 years of age and older who were enrolled in clinical research with patients with a particular ailment were treated with Quizartinib. The senior population and younger adults did not exhibit any appreciable variations in safety or efficacy, according to the study.
Impaired Renal Function: The Cockcroft-Gault equation, which assesses renal function, normally does not call for a modification in Quizartinib dosage in individuals with mild to moderate kidney impairment. Data on the use of Quizartinib in individuals with severe renal impairment are, however, lacking.
Hepatic Impairment: Modest to moderate liver damage normally does not need changing the Quizartinib dose. However, there has not been much research done on the drug in people with severe liver impairment, so people should use caution in these situations.

Quizartinib: A Beacon of Hope for FLT3-ITD AML Fighters