Usage
Alpelisib is prescribed for two main conditions:
- HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer: In combination with fulvestrant, it’s used in postmenopausal women and men after progression on or after endocrine-based therapy. A FDA-approved test must confirm PIK3CA mutation.
- PIK3CA-Related Overgrowth Spectrum (PROS): It treats severe manifestations in patients 2 years and older requiring systemic therapy.
Pharmacological Classification: Kinase inhibitor, specifically a PI3K inhibitor.
Mechanism of Action: Alpelisib inhibits the alpha isoform of phosphatidylinositol 3-kinase (PI3K), a key enzyme in cell growth and proliferation. In certain cancers and overgrowth syndromes, mutations in the PIK3CA gene lead to overactivation of this pathway. By selectively blocking PI3Kα, alpelisib helps to normalize cell signaling and reduce uncontrolled growth.
Alternate Names
- Generic Name: Alpelisib
- Brand Names: Piqray (for breast cancer), Vijoice (for PROS)
How It Works
Pharmacodynamics: Alpelisib inhibits PI3Kα signaling, leading to downstream effects such as reduced cell proliferation, altered metabolism, and potential impacts on angiogenesis.
Pharmacokinetics:
- Absorption: Alpelisib is administered orally and is best absorbed when taken with food.
- Metabolism: Primarily metabolized by CYP3A4 and CYP2C8 enzymes in the liver.
- Elimination: Excreted predominantly in the feces, with a smaller portion eliminated in the urine. Elimination half-life is approximately 24 hours.
Mode of Action: Alpelisib binds to and inhibits the catalytic subunit p110α of PI3K, preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). This inhibition disrupts downstream signaling pathways, including Akt/mTOR, which are crucial for cell growth and survival.
Receptor Binding, Enzyme Inhibition: Alpelisib demonstrates selective inhibition of PI3Kα.
Elimination Pathways: Hepatic metabolism via CYP3A4 and CYP2C8, with fecal excretion as the primary route of elimination.
Dosage
Standard Dosage
Adults:
- Breast Cancer: 300 mg (two 150 mg tablets) orally once daily with food.
- PROS: 250 mg orally once daily with food.
Children (PROS):
- Under 6 years: 50 mg orally once daily with food.
- 6 years and older: 50 mg orally once daily with food, increasing to 125 mg after 24 weeks if needed for response optimization.
Special Cases:
- Elderly Patients: No specific dose adjustments are recommended, but closer monitoring for adverse events, particularly gastrointestinal toxicity and hyperglycemia, is advised.
- Patients with Renal Impairment: Caution is advised in severe renal impairment. Dose adjustment may not be needed for mild or moderate renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustment is required for mild, moderate, or severe hepatic impairment.
- Patients with Comorbid Conditions: Careful monitoring of blood glucose is essential, especially in patients with diabetes or pre-existing hyperglycemia.
Clinical Use Cases
Alpelisib is not indicated for use in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its usage is specific to the treatment of breast cancer and PROS, as described above.
Dosage Adjustments
Dose reductions may be necessary for managing adverse events like hyperglycemia, diarrhea, rash, and other toxicities. See side effects section for detailed guidelines on dose modifications based on specific adverse reactions.
Side Effects
Common Side Effects
Nausea, vomiting, diarrhea, decreased appetite, weight loss, hyperglycemia, rash, fatigue, stomatitis, alopecia, headache.
Rare but Serious Side Effects
Severe hypersensitivity reactions (including anaphylaxis), severe cutaneous adverse reactions (SCARs, including Stevens-Johnson syndrome and toxic epidermal necrolysis), pneumonitis, severe hyperglycemia (including diabetic ketoacidosis), increased risk of infections.
Long-Term Effects
The long-term effects of alpelisib are still under investigation. However, potential concerns include impacts on fertility and the theoretical risk of secondary malignancies due to chronic PI3K pathway inhibition.
Adverse Drug Reactions (ADR)
SCARs, anaphylaxis, severe hyperglycemia, pneumonitis require immediate intervention.
Contraindications
- Known hypersensitivity to alpelisib.
- Coadministration with strong CYP3A4 inducers (e.g., rifampicin, phenytoin).
Drug Interactions
- CYP3A4 Inducers: Reduce alpelisib exposure and may decrease efficacy. Avoid concomitant use.
- CYP3A4 Inhibitors: Increase alpelisib exposure and may increase toxicity. Monitor closely or avoid combined use.
- CYP2C8 Inhibitors: May increase alpelisib exposure and increase toxicity. Monitor closely.
- BCRP Inhibitors: May increase alpelisib exposure and increase toxicity. Monitor closely or avoid combined use.
- CYP2C9 Substrates: Alpelisib may induce CYP2C9, leading to decreased concentrations of co-administered CYP2C9 substrates (e.g., warfarin). Monitor and adjust dosage accordingly.
- Acid-reducing agents (e.g. ranitidine): May slightly reduce alpelisib absorption.
Pregnancy and Breastfeeding
- Pregnancy: Alpelisib is contraindicated in pregnancy due to the risk of fetal harm. Effective contraception is essential during treatment and for at least one week after the final dose for both men and women.
- Breastfeeding: Alpelisib should not be used during breastfeeding and for at least one week after the last dose due to the potential for adverse reactions in infants.
Drug Profile Summary
- Mechanism of Action: PI3Kα inhibitor.
- Side Effects: Nausea, vomiting, diarrhea, hyperglycemia, rash, fatigue, stomatitis, increased infection risk, SCARs, hypersensitivity reactions.
- Contraindications: Hypersensitivity, strong CYP3A4 inducers, pregnancy.
- Drug Interactions: CYP3A4/2C8/BCRP inhibitors and inducers, CYP2C9 substrates.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Breast cancer: 300mg daily; PROS: 250mg daily (adults) / 50-125mg daily (children).
- Monitoring Parameters: Blood glucose, liver function tests, complete blood count, signs of rash or hypersensitivity.
Popular Combinations
- Alpelisib + Fulvestrant (for breast cancer).
Precautions
- General Precautions: Monitor blood glucose, liver function, and complete blood counts regularly. Be vigilant for signs of rash, hypersensitivity, or infections.
- Specific Populations: See Dosage - Special Cases.
- Lifestyle Considerations: No specific dietary restrictions are mentioned but taking the medication with food is recommended for optimal absorption. Alcohol should be consumed in moderation due to the potential increased risk of liver toxicity. Driving limitations are not usually necessary unless severe side effects impacting alertness or cognition are observed.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Alpelisib?
A: For breast cancer: 300 mg once daily with food for adults. For PROS: 250 mg once daily with food for adults, 50 mg once daily with food for children under 6, and 50 mg once daily with food for children 6 years and older, potentially increasing to 125 mg after 24 weeks.
Q2: What are the common side effects of Alpelisib?
A: Common side effects include nausea, vomiting, diarrhea, hyperglycemia, rash, fatigue, and stomatitis.
A: Severe hypersensitivity reactions, SCARs (including Stevens-Johnson syndrome and toxic epidermal necrolysis), pneumonitis, and severe hyperglycemia.
Q4: Can Alpelisib be used during pregnancy or breastfeeding?
A: No, Alpelisib is contraindicated during pregnancy and breastfeeding due to potential harm to the fetus or infant.
Q5: What are the major drug interactions with Alpelisib?
A: Alpelisib interacts significantly with CYP3A4 and CYP2C8 inhibitors and inducers, BCRP inhibitors, and CYP2C9 substrates.
Q6: How should Alpelisib be administered?
A: Alpelisib should be administered orally with food, at approximately the same time each day. The tablets should be swallowed whole and not crushed, chewed, or split.
Q7: What should be done if a dose of Alpelisib is missed?
A: If a dose is missed within 9 hours of the usual time, take the missed dose with food. If more than 9 hours have passed, skip the missed dose and resume the regular schedule the next day.
Q8: Does Alpelisib require any specific monitoring?
A: Patients on Alpelisib require regular monitoring of blood glucose levels, liver function tests, and complete blood counts. Close observation for signs of rash, hypersensitivity, or infections is also essential.
Q9: What are the contraindications to using Alpelisib?
A: Contraindications include hypersensitivity to alpelisib and coadministration with strong CYP3A4 inducers.
Q10: How does hepatic or renal impairment affect Alpelisib dosage?
A: No dose adjustment is typically required for mild to severe hepatic impairment. Caution is advised in severe renal impairment, while no dose adjustment is necessary for mild or moderate renal impairment.
