Duvelisib- Uses, Indications, Contraindications, Pharmacology, and Side Effects

Overview:

Duvelisib is a prescription medication for certain blood cancers, including chronic lymphocytic leukemia (CLL) and another is follicular lymphoma (FL). It is a targeted therapy that blocks certain enzymes that causes the growth and survival of cancer cells.

CLL and FL are both types of non-Hodgkin's lymphoma of cancers that affect the lymphatic system), which is responsible for producing and transporting immune cells throughout the body. CLL is a slowly progressive cancer affecting white blood cells, while FL is a more aggressive cancer affecting lymph nodes and bone marrow. Duvelisib was approved by the U.S. Food and Drug Administration (FDA) on September 24, 2018, for treating CLL and FL. It is administered orally in capsule form and is typically taken twice daily.

How Does Duvelisib work?

Duvelisib targets specific enzymes in the signaling pathways that regulate cell growth and survival. These enzymes, known as PI3Ks (phosphoinositide 3-kinases), play a key role in the growth and division of cancer cells. By blocking these enzymes, Duvelisib helps to stop the growth and division of cancer cells, ultimately destroying cancer cells.

What Are the Indications and Contraindications of Duvelisib?

Indications:

• Duvelisib is indicated for treating chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

• CLL is a type of slow-growing cancer affecting white blood cells, and FL is a more aggressive cancer affecting lymph nodes and bone marrow.

• Duvelisib is used to treat patients who have taken at least two prior therapies for CLL or FL or for patients who have relapsed after prior treatment.

• Duvelisib can be used as a monotherapy or in combination with other therapies, depending on each patient's specific needs.

Contraindications:

• Duvelisib is contraindicated in patients with a known hypersensitivity to Duvelisib or any of its components.

• Duvelisib can increase the risk of serious infections. Therefore, it is contraindicated in patients with active infections.

• The liver metabolizes Duvelisib, and patients with severe hepatic impairment may experience increased exposure to the drug.

• Duvelisib cause fetal harm. It is also unknown if Duvelisib is excreted in human milk. Therefore, Duvelisib is contraindicated in pregnant and breastfeeding women.

What Are the Warnings and Precautions for Duvelisib?

Duvelisib has several warnings that patients and healthcare providers should be aware of. Some of these include:

• Infections: Duvelisib may increase the risk of serious infections, including opportunistic infections like Pneumocystis jiroveci pneumonia (a fungal infection affecting the lungs). Patients must be monitored for signs of infection and treated promptly if an infection occurs.

• Diarrhea and Colitis: Duvelisib can cause diarrhea and colitis, which may be severe and lead to dehydration and hospitalization. Patients should be monitored for signs of diarrhea and colitis, and treatment should be started promptly if symptoms occur.

• Pneumonitis: Duvelisib can cause pneumonitis, a condition in which the lungs become inflamed. Patients should be monitored for signs of pneumonitis, including cough, breathlessness, and fever, and treatment should be started promptly if symptoms occur.

• Hepatotoxicity: Duvelisib can cause hepatotoxicity, which may be severe and lead to liver failure. Patients require monitoring for signs of hepatotoxicity, such as jaundice and elevated liver enzymes, and treatment should be started promptly if symptoms occur.

• Embryo-Fetal Toxicity: Duvelisib can cause fetal harm when administered to a pregnant woman. Women of reproductive age should use effective contraception during treatment with Duvelisib.

• Immunizations: Patients should not receive live vaccines while taking Duvelisib, and healthcare providers should consider administering non-live vaccines at least two weeks before starting Duvelisib.

• Adverse Reactions: Duvelisib can cause various adverse reactions, including nausea, fatigue, fever, and rash.

For Patients:

What Is CLL?

Chronic lymphocytic leukemia is a cancer affecting the blood and bone marrow. Slow-growing cancer develops from white blood cells called B lymphocytes or B cells. In CLL, these B cells grow and divide abnormally, accumulating abnormal lymphocytes in the blood, bone marrow, and lymph nodes.

As abnormal lymphocytes increase, they may crowd out normal blood cells, leading to anemia, infections, and bleeding problems. CLL can also cause lymph nodes to become swollen and painful. The cause of CLL is not fully known. CLL is most commonly diagnosed in people over 60.

What Should a Person Tell Before Taking It?

• If the person with an active infection or a history of recurrent infections.

• If the person is allergic to Duvelisib or its components.

• If the person is pregnant or breastfeeding.

• If the person has received any vaccines recently.

• If the person takes any other medications, including over-the-counter medications, vitamins, or supplements.

• If the person has a bleeding disorder or is taking medications, that can increase the risk of bleeding.

How Will the Duvelisib Drug Be Administered?

• Duvelisib is taken orally in the form of a tablet. The tablets must be swallowed whole, not crushed, chewed, or broken.

• Duvelisib can be taken either food or without food.

• The dosage and duration of treatment with Duvelisib will be based on the individual patient's medical condition and response to treatment.

• Patients should follow their doctor's instructions on how to take Duvelisib, including the dose and duration of treatment.

• Patients should not adjust the dose or stop taking Duvelisib without consulting their doctor.

Dosage and Forms:

Duvelisib is available in tablet form, each containing 25 milligrams (mg) or 100 mg of the active ingredient Duvelisib.

The recommended dosage of Duvelisib for treating refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) is 25 mg, taken orally twice a day, with or without food.

For treating relapsed or refractory follicular lymphoma (FL), the recommended dosage of Duvelisib is 25 mg, taken twice a day.

For Doctors:

Pharmacodynamics

Duvelisib is a selective inhibitor of two enzymes, PI3K-delta and PI3K-gamma, which play important roles in the proliferation, survival, and activation of lymphocytes. By inhibiting these enzymes, Duvelisib reduces the signaling pathways which drive the growth and survival of cancer cells in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL).

In laboratory studies, Duvelisib has been shown to induce cell death in CLL and SLL cells and inhibit the growth and proliferation of follicular lymphoma cells. Duvelisib has demonstrated significant antitumor activity in patients with relapsed or refractory CLL, SLL, and FL in clinical trials.

Duvelisib also affects the immune system by inhibiting the cytokines and chemokines production that are involved in the inflammatory response. This anti-inflammatory effect may contribute to the drug's ability to reduce the size of lymph nodes and spleen in patients with CLL and SLL.

Pharmacokinetics

Duvelisib is an orally administered drug rapidly absorbed and extensively distributed throughout the body. The pharmacokinetics of Duvelisib has been evaluated in clinical studies, and the following details the pharmacokinetic parameters observed.

• Absorption: Duvelisib is rapidly absorbed after oral administration, with peak plasma concentrations reached within two hours. The bioavailability of Duvelisib is increased when taken with food, so it is recommended to take Duvelisib with food.

• Distribution: Duvelisib is extensively distributed throughout the body. The volume of distribution is about 600 liters, which suggests that the drug is distributed beyond the plasma compartment into the tissues.

• Metabolism: Duvelisib is metabolized in the liver by the enzyme CYP3A4 and, also by CYP2C8.

• Elimination: Duvelisib is eliminated primarily in the feces (78 %) and, to a lesser extent, in the urine (16 %). The half-life of Duvelisib is about six to eight hours. The clearance of Duvelisib is about 43 L/h, which indicates moderate clearance.

What Are the Potential Drug Interactions of Duvelisib?

The following are some drugs that may interact with Duvelisib:

• Strong CYP3A4 Inhibitors: Combining Duvelisib with strong CYP3A4 inhibitors may increase Duvelisib exposure, increasing the risk of adverse reactions. Examples of strong CYP3A4 inhibitors include Ketoconazole, Itraconazole, Clarithromycin, and Grapefruit juice.

• Strong CYP3A4 Inducers: Co-administration of Duvelisib with strong CYP3A4 inducers may decrease Duvelisib exposure, which may decrease the efficacy of Duvelisib. Examples of strong CYP3A4 inducers include Rifampin, Phenytoin, Carbamazepine, and St. John's Wort.

• Drugs that Affect Gastric PH: Duvelisib should be taken with food, as the bioavailability of Duvelisib is increased when taken with food. Drugs that increase gastric pH may decrease the bioavailability of Duvelisib, so they should be avoided. Examples of drugs that affect gastric pH include Proton pump inhibitors and Antacids.

• Other Drugs: Duvelisib may interact with other drugs metabolized by CYP3A4 and CYP2C8, such as Warfarin, Simvastatin, and Cyclosporine.

Toxicity:

Duvelisib may cause toxicity or overdose if taken in excessive doses or if it accumulates in the body due to impaired elimination. Symptoms of Duvelisib toxicity may include diarrhea, nausea, vomiting, abdominal pain, fatigue, decreased appetite, fever, and rash. It may lead to liver toxicity, immune suppression, and opportunistic infections. If a person suspects they may have overdosed on Duvelisib, they should seek medical attention immediately.

Management of Toxicity:

Managing Duvelisib toxicity involves supportive measures to manage the symptoms and close monitoring of vital signs and laboratory values. The following measures may be used to manage Duvelisib toxicity:

• Discontinuation of Duvelisib: If a patient is experiencing significant toxicity, the doctor may consider stopping

• Supportive Care: Symptomatic treatment may be given to manage nausea, vomiting, diarrhea, and fever. Hydration and electrolyte replacement may also be necessary to maintain fluid balance and prevent dehydration.

• Hematologic Support: If a patient develops myelosuppression or thrombocytopenia due to Duvelisib toxicity, the doctor may consider growth factor support or blood transfusions to manage these complications.

• Management of Hepatic Toxicity: In cases of liver toxicity, the doctor may monitor liver function tests and consider discontinuing Duvelisib or reducing the dose to prevent further damage to the liver.

• Opportunistic Infection Prophylaxis: Patients at high risk of opportunistic infections, such as those with low white blood cell counts, may require prophylactic antibiotics or antifungal agents to prevent infections.

Non-Clinical Toxicity:

Non-clinical toxicity studies have shown that Duvelisib can cause liver and kidney damage, immune suppression, and hematologic toxicity in animals. These are explained as follows-

• Liver Toxicity: In non-clinical toxicity studies, high doses of Duvelisib have been associated with liver damage in animals. The liver metabolizes the drugs, and high doses of Duvelisib can overwhelm its capacity, leading to liver damage. This can manifest as increased liver enzymes (AST and ALT) or more severe forms of liver injury.

• Kidney Toxicity: Duvelisib has been associated with animal kidney damage in non-clinical toxicity studies. The kidneys are responsible for excreting drugs from the body, and high doses of Duvelisib can damage them, leading to reduced kidney function. This can manifest as an increase in serum creatinine or other markers of kidney function.

• Immune Suppression: Duvelisib targets a specific type of white blood cell called lymphocytes, which play a crucial role in the immune system. Non-clinical toxicity studies have shown that Duvelisib suppresses the immune system by decreasing the number of lymphocytes, making the body more vulnerable to infections and other illnesses.

• Hematologic Toxicity: Duvelisib can cause hematologic toxicity, adversely affecting the blood and blood-forming organs. Non-clinical toxicity studies have shown that Duvelisib can reduce the number of red blood cells, WBC (white blood cells), and platelets, causing anemia, infections, and bleeding disorders.

What Are the Cautions to Be Considered While Using Duvelisib?

• Pregnancy - There is less information available on the use of Duvelisib in pregnant women, and it is not recommended for use during pregnancy, only used when the potential benefit is greater than the risk to the fetus. Animal studies have shown that Duvelisib can cause fetal harm and may impair fertility. Therefore, women of reproductive age should use effective contraception during Duvelisib treatment and at least one month after the last dose. If a patient becomes pregnant while taking Duvelisib, she should be advised of the potential risk to the fetus and the need to inform her healthcare provider immediately.

• Breastfeeding - It is unknown whether Duvelisib is excreted in human milk, and the effects on a nursing infant are also unknown. Breastfeeding is not recommended during treatment with Duvelisib one month after the last dose. Women should be advised to discontinue breastfeeding or discontinue Duvelisib therapy, taking into account the importance of Duvelisib to the mother.

• Pediatrics - The safety and effectiveness of Duvelisib in pediatric patients have not been established. Limited information is present on the use of Duvelisib in patients under 18, and it is not recommended for use in this population. Duvelisib has been shown to cause adverse reactions such as infections, neutropenia, and diarrhea, which may be more severe in pediatric patients.

Conclusion:

Duvelisib is a small molecule inhibitor of the PI3K delta and gamma isoforms, classified as an antineoplastic agent and an immunomodulator. It treats certain types of cancer and autoimmune diseases by inhibiting the activity of PI3K enzymes, which are critical in regulating cell growth and survival. While Duvelisib can be effective in treating these conditions, it can also cause adverse effects, and close monitoring of patients receiving Duvelisib is necessary to manage these adverse effects appropriately.