Alpelisib in Advanced Breast Cancer: An Overview

Introduction:

Alpelisib is a cancer-fighting drug that inhibits phosphatidylinositol 3-kinase (PI3K), especially its p110α subunit. Several malignancies frequently have mutations in this enzyme, which results in aberrant cell proliferation. Alpelisib's purpose is to target and block this mutant enzyme specifically. For the treatment of advanced or metastatic breast cancer in postmenopausal women and men, Alpelisib medication is used in conjunction with Fulvestrant. It is essential to use FDA-approved diagnostic tests to confirm the existence of a specific mutation (PIK3CA) before beginning Alpelisib medication.

Current research is examining the efficacy of Aleplisib in treating malignancies other than breast cancer, such as colorectal and ovarian cancer. The FDA approved Alpelisib on May 24, 2019. The FDA approved the use of Alepelisib in April 2022 for treating adults and children with PIK3CA-Related Overgrowth Spectrum (PROS) who need systemic therapy.

For Patients:

Why Is a Prescription for Alpelisib Given?

Alpelisib and Fulvestrant are used in combination to treat a specific kind of breast cancer in men whose cancer worsened during or after certain other treatments or in women who have already undergone menopause (also known as the "change of life," or the end of their menstrual periods) and have spread to nearby tissues or other parts of the body. Adults and children two years of age and up with certain forms of PIK3CA Related Overgrowth Spectrum (PROS), a hereditary disorder causing overgrowth and abnormalities in specific bodily tissues, are treated with Alpelisib.

Drug Group

Alpelisib belongs to a group of drugs known as kinase inhibitors. It functions as a cancer treatment by blocking the signals that cause cancer cells to multiply, stopping cancer cell spread. By blocking the impulses that cause overgrowth and abnormalities in particular body tissues, the size of the overgrowth is reduced, and symptoms in PROS patients are relieved.

How Is Alpelisib Administered?

Alpelisib is available as an oral tablet. Usually, it is taken once a day with food as per the physician's prescribed treatment plan. Take Alpelisib daily at approximately the same time. Administer Alpelisib as prescribed. Never take more or less of it or more frequently than the doctor has instructed.

Do not split, chew, or crush the tablets; swallow them whole. Take care not to take any damaged, cracked, or broken tablets. One can dissolve the pills in water if one is taking Alpelisib for PROS and finds it difficult to take the whole tablet. Put the tablet(s) into a glass of water that has two to four ounces (60 to 120 milliliters) in it. After five minutes, smash the tablets and use a spoon to stir the mixture. Consume the blend right away. Add two to three tablespoons of water to the glass using the same spoon and whisk to rinse.

To remove any remaining particles from the glass, add two to three tablespoons of water and stir with the same spoon. To ensure one gets all of the medication, drink the entire concoction. If needed, repeat.

Do not take another dose of Alpelisib if an individual throws up after taking it. Maintain the usual dosage regimen. If one encounters certain side effects, the doctor may reduce the amount of Alpelisib one takes. Doctors might treat the individuals with different drugs or halt or modify the treatment. Ensure one lets the doctor know how one feels while receiving Alpelisib medication.

Safety Measures to Be Taken

Before Utilizing Alpelisib:

• If one has an allergy to any of the substances in Alpelisib tablets, other drugs, herbal products, or Alpelisib itself, let the doctor and chemist know. Get an ingredient list from the chemist.

• Inform the physician and chemist of all prescribed and over-the-counter drugs, vitamins, and dietary supplements that one now takes or intends to take. The doctor might need to carefully monitor one for any negative effects or adjust the dosages of the medications.

• Inform the physician if one currently has diabetes or kidney illness or if one has ever experienced a rash with red sores on the lips, mouth, or skin or flaking, blistering skin.

• Patients on Alpelisib should let their doctors know if they intend to get pregnant or if they are already pregnant with their partners. It is important to remember that while taking Alpelisib, neither the patient nor their partner should try to get pregnant. One must take a pregnancy test before starting therapy if one is a female. One should also use reliable birth control during the treatment and for one week following the last dosage. Use an effective birth control method and a condom during treatment and for one week following the last dose if one is a male and the female partner is capable of getting pregnant. Inform the doctor if the partner falls pregnant while taking Aleplisib.

• Breastfeeding should not be done during therapy or for one week following the last dose, according to one expert. One should be aware that this medicine may lower both men's and women's fertility. See the physician about the potential hazards of using Aleplisib.

What Are the Side Effects of Alpelisib?

• An individual needs to be aware that Alpelisib may elevate blood sugar. Check the blood sugar as frequently as the physician prescribes if one has diabetes or high blood sugar. Give the doctor a call if the blood sugar is higher than normal.

• If one experiences any of the following side effects while taking Alpelisib, contact the doctor immediately: weakness, blurred vision, excessive thirst, frequent urination, or severe hunger. Since untreated high blood sugar can lead to a dangerous disease known as ketoacidosis, it is advised to contact the doctor urgently in case symptoms appear.

• If ketoacidosis is not treated on time, it could turn fatal. Ketoacidosis is characterized by diminished consciousness, breath that smells like fruit, upset stomach and vomiting, and dry mouth.

• When using Alpelisib, if one gets nausea, vomiting, or diarrhea that prevents one from eating or drinking regularly, contact the doctor.

• While using Alpelisib, the doctor might need to adjust the diet or medicine to assist in controlling the blood sugar.

How Should One Proceed If One Overlook a Dosage?

An individual should take the missed dose as soon as they recall. On the other hand, omit the missed dose and stick to the usual dosing plan if it has been more than nine hours after the missed dose. Never take two doses to make up for the missed dose.

What Untoward Consequences Might This Medicine Have?

Side effects are possible with Alpelisib. If any of these symptoms are severe or persistent, let the doctor know:

• Nausea.

• Throwing up.

• Excessive fatigue.

• Diminished hunger.

• Alteration in the flavor of the food.

• Weight reduction.

• Stomach ache.

• Reflux.

• Hair thinning.

• Migraine.

• Itching.

• Dry skin.

• Mouth dryness.

• Oral sores.

• Dryness in the vagina.

• Fever.

• Arm or leg edema.

Certain adverse effects may be dangerous. Call the doctor right away or seek emergency medical attention if one encounters any of the following symptoms, as well as those mentioned in the special precaution section:

• Breathing or swallowing difficulties, rash, hives, flushing, fever, or rapid pulse

• Swelling in the hands, feet, ankles, eyes, throat, tongue, lips, and lower limbs

• Rash; lips, eyes, or mouth blistering; blistering, peeling, or reddish skin.

• Fever.

• Flu-like symptoms.

• Breathing difficulties and shortness of breath.

• Chest pain.

• Coughing.

• Severe diarrhea, parched lips,

• Cramps.

• Weakness.

• Decreased urine production.

• Ankle or leg swelling.

• Diarrhea that is red or watery, stomach ache.

• Urinating frequently, painfully, or urgently.

Other side effects are possible with Alepelisib. Contact the doctor immediately if one has any odd side effects while taking this medicine.

What Is the Proper Way to Store and Discard This Medication?

Store this medication tightly closed, out of the children’s reach, and in the original container. Keep it out of the bathroom, away from excessive heat, and at room temperature. As many prescription containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and small children can readily open them, it is crucial to keep all medication out of sight and reach of children. Always lock the safety caps on medications to prevent poisoning in small children.

Indication:

For the treatment of postmenopausal women and men with advanced or metastatic breast cancer, Aleplisib, in conjunction with Fulvestrant, is recommended. Hormone Receptor (HR) positivity, Human Epidermal Growth Factor Receptor 2 (HER2) negativity, and PIK3CA mutation are required for this cancer. After the cancer progresses on or after an endocrine-based therapy, it must be found using a test approved by the FDA.

In addition, systemic medication is utilized to treat adults and children two years of age and older who have severe signs of PIK3CA-Related Overgrowth Spectrum (PROS). This indication is approved under rapid approval based on the reaction's length and the response rate. The confirmation and description of the therapeutic benefit of a confirmatory trial may be required before the indication's continued approval.

Related Disorders

HER2-, HR+, and Advanced Breast Cancer.

PROS, or PIK3CA-Related Overgrowth Spectrum.

Breast cancer with metastatic HR and HER2.

For Doctors

• Pharmacodynamics: The QTcF interval is not prolonged by Alepelisib. Patients on Alpelisib benefit from treatment in proportion to the dose, with a 200 mg (milligrams) daily dose having a 51 % advantage over a 100 mg (milligrams) dose and a 300 mg once-daily dose having a 22 % advantage over a 150 mg twice daily dose. This implies that twice-day dosing may benefit people requiring a lesser dose.

• Mechanism of Action: Phospholipidinositol-3-kinase (PI3K) is inhibited by Alepelisib, which primarily inhibits PI3Kα. Gain-of-function mutations in the PIK3CA gene, which codes for the catalytic α-subunit of PI3K, result in cellular transformation, tumor development in both in vitro and in vivo models, and activation of PI3Kα and Akt-signaling. Alpelisib demonstrated efficacy in cell lines with a PIK3CA mutation and suppressed the phosphorylation of PI3K downstream targets, including Akt, in breast cancer cell lines. In xenograft models, including breast cancer models, Alpelisib suppressed the PI3K/Akt signaling pathway and decreased tumor development in vivo. It has been demonstrated that treating breast cancer cells with Alpelisib to suppress PI3K causes an increase in ER transcription. In xenograft models made from ER-positive, PIK3CA-mutated breast cancer cell lines, Alpelisib plus Fulvestrant showed more antitumor activity than either treatment alone.

• Absorption: After two hours, Alpelisib's plasma concentration peaked at 1320±912ng/mL (nanogram per milliliter). The AUClast and AUCinfof Alpelisib are 11,100±3760h and 11,100±3770h ng/mL, respectively. A little lunch with low-fat content raises the AUC by 77 % and Cmax by 145 %, whereas a substantial meal with high-fat content increases the AUC by 73 % and Cmax by 84 %.

• Volume of Distribution: At a steady state, the apparent volume of distribution is 114L.

• Binding of Proteins: 89 % of Alpelisib is bound to proteins.

• Metabolism: The major metabolite of Alepelisib is produced through hydrolysis processes. CYP3A4.7 also metabolizes it. Although the entire metabolism of Alpelisib is unknown, several reactions have been suggested. The primary metabolic process involves replacing a hydroxyl group on Alpelisib with an amine group, resulting in the formation of the metabolite M44,5 or BZG791. Alpelisib can also be converted into the M1 and M12 metabolites via glucuronidation.

• Route of Elimination: Oral dosage is excreted in the feces in two ways: 36 % as the unaltered medication and 32 % as the main metabolite BZG791. Roughly 2 % of an oral dosage is excreted in the urine as the medication is unaltered, and 7.1 % is excreted as the main metabolite BZG791. An oral dose is excreted in the feces 81 % of the time, and the urine 14 %.

• Half-life: Alpelisib has an average half-life of eight to nine hours.
• Clearance: 39.0 L/h (liters per hour) was the average apparent oral clearance.4 9.2 L/hr is the estimated clearance in fed conditions.
• Hazards: Overdosed individuals may exhibit rash, nausea, asthenia, and hyperglycemia. Alpelisib overdoses have no known antidote; hence, the patients get only symptomatic treatment. Information on an LD50 is not easily accessible. Patients received doses of up to 450 mg once daily during clinical trials.

Conclusion:

In conjunction with fulvestrant for the treatment of postmenopausal men and women whose breast cancer has progressed on or after an endocrine-based regimen and has been identified by an FDA-approved test as Hormone Receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced, or metastatic.