Indications
Alpelisib is prescribed in combination with fulvestrant for the treatment of advanced or metastatic breast cancer in postmenopausal women and men. The specific type of breast cancer targeted is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), and must exhibit a PIK3CA mutation. This mutation must be identified using an FDA-approved test, and the patient must have experienced progression following an endocrine-based regimen. Additionally, Alpelisib is administered to both adults and pediatric patients aged two years and older who exhibit severe symptoms relating to the PIK3CA-Related Overgrowth Spectrum (PROS), requiring systemic treatment. Approval for the latter indication was granted under accelerated conditions based on observed response rates, with continued approval contingent upon further confirmation of clinical benefits in subsequent trials.
Pharmacodynamics
Alpelisib exhibits pharmacodynamic properties where it does not extend the QTcF interval. Treatment with Alpelisib provides a dose-dependent benefit, showing a 51% efficacy improvement when a 200mg daily dose is used compared to a 100mg daily dose. Similarly, a single daily dose of 300mg shows a 22% efficacy advantage over a 150mg dose administered twice daily. This indicates that patients who require a reduced dosage regimen may benefit more from twice-daily dosing to optimize their therapeutic response.
Absorption
Alpelisib reaches a peak plasma concentration of 1320±912 ng/mL approximately two hours after administration. The area under the curve (AUC) from the last measured point (AUClast) is 11,100±3760 h·ng/mL, and from time zero to infinity (AUCINF), it is 11,100±3770 h·ng/mL. Consumption of a large, high-fat meal can increase Alpelisib's AUC by 73% and its maximum concentration (Cmax) by 84%. Conversely, ingestion with a small, low-fat meal results in a 77% increase in AUC and a 145% increase in Cmax, suggesting that dietary conditions significantly influence its absorption.
Metabolism
Alpelisib undergoes hydrolysis reactions to form a primary metabolite and is additionally metabolized by the enzyme CYP3A4. While the complete metabolic pathway for Alpelisib has not yet been thoroughly characterized, it involves several reactions. A primary metabolic transformation involves substituting an amine group on Alpelisib with a hydroxyl group, creating a metabolite known as M4 or BZG791. Furthermore, Alpelisib can undergo glucuronidation, producing metabolites M1 and M12, suggesting a complex metabolic profile.
Mechanism of Action
Alpelisib functions by selectively inhibiting the phosphatidylinositol-3-kinase-α (PI3Kα) enzyme, which plays a crucial role in cell proliferation following activation by the growth factor-tyrosine kinase signaling pathway. In certain cancers, the p110α catalytic subunit of PI3Kα is mutated, resulting in its hyperactivation. Alpelisib specifically targets PI3Kα, offering precision in its mechanism of action when addressing these oncogenic mutations.
