Alpelisib
Alpelisib Uses, Dosage, Side Effects, Food Interaction and all others data.
Alpelisib is a phosphatidylinositol 3-kinase (PI3K) inhibitor with potent antitumor activity. It works by selectively inhibiting class I PI3K p110α , which is the catalytic subunit of PI3K, a lipid kinase that plays a role in various biological processes, including proliferation, survival, differentiation, and metabolism. Alpelisib was designed to target this enzyme that appears to be mutated at a rate of nearly 30% in human cancers, leading to hyperactivation.
There are several isoform-specific PI3K inhibitors that are under clinical development or currently approved, such as idelalisib used for chronic lymphocytic leukemia (CLL). Approved by the FDA in May 2019, alpelisib is the first approved PI3K inhibitor indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer in combination with fulvestrant for postmenopausal women and male patients. To initiate alpelisib therapy, it is required that the presence of a PIK3CA mutation in the tissue and/or liquid biopsy sample collection should be confirmed via FDA-approved diagnostic tests. Alpelisib is marketed under the trade name Piqray and is available as oral tablets. Studies evaluating the therapeutic effectiveness of alpelisib in other cancers, such as ovarian cancer and colorectal cancer , are under ongoing investigations.
Alpelisib was granted FDA approval on 24 May 2019.
| Trade Name | Alpelisib |
| Availability | Prescription only |
| Generic | Alpelisib |
| Alpelisib Other Names | Alpelisib |
| Related Drugs | tamoxifen, Arimidex, Ibrance, Femara, Xeloda, Herceptin, Lynparza, palbociclib, Nolvadex, Piqray |
| Weight | 150mg, 200mg, 200mg + 50mg |
| Type | Oral tablet |
| Formula | C19H22F3N5O2S |
| Weight | Average: 441.47 Monoisotopic: 441.144630278 |
| Protein binding | Alpelisib is 89% protein bound. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Alpelisib is indicated in combination with fulvestrant to treat postmenopausal women, and men, with advanced or metastatic breast cancer. This cancer must be hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and PIK3CA mutated. The cancer must be detected by an FDA-approved test following progression on or after an endocrine-based regimen.
Alpelisib is also used to associated treatment for these conditions: Advanced Metastatic Breast Cancer
How Alpelisib works
Phosphatidylinositol-3-kinase-α (PI3Kα) is responsible for cell proliferation in response to growth factor-tyrosine kinase pathway activation. In some cancers PI3Kα's p110α catalytic subunit is mutated making it hyperactive. Alpelisib inhibits (PI3K), with the highest specificity for PI3Kα.
Toxicity
LD50 and Overdose
Patients experiencing an overdose may present with hyperglycemia, nausea, asthenia, and rash. There is no antidote for an overdose of alpelisib so patients should be treated symptomatically. Data regarding an LD50 is not readily available. In clinical trials, patients were given doses of up to 450mg once daily.
Pregnancy, Lactation, and Fertility
Following administration in rats and rabbits during organogenesis, adverse effects on the reproductive system, such as embryo-fetal mortality, reduced fetal weights, and increased incidences of fetal malformations, were observed. Based on these findings of animals studies and its mechanism of action, it is proposed that alpelisib may cause embryo-fetal toxicity when administered to pregnant patients. There is no data available regarding the presence of alpelisib in breast milk so breast feeding mothers are advised not to breastfeed while taking this medication and for 1 week after their last dose. Based on animal studies, alpelisib may impair fertility of humans.
Carcinogenicity and Mutagenicity
Studies of carcinogenicity have yet to be performed. Alpelisib has not been found to be mutagenic in the Ames test. It is not aneugenic, clastogenic, or genotoxic in further assays.
Food Interaction
- Exercise caution with St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of alpelisib.
- Take at the same time every day.
- Take with food. Food does not significantly affect the AUC of alpelisib.
[Moderate] ADJUST DOSING INTERVAL: Food significantly enhances the oral absorption and bioavailability of alpelisib.
When administered with a high-fat high-calorie meal (985 calories with 58.1 g of fat) or a low-fat low-calorie meal (334 calories with 8.7 g of fat) the AUC and Cmax of a single dose of alpelisib was increased by 73% and 84% and 77% and 145%, respectively.
There were no clinically significant differences in alpelisib AUC between the two types of meals.
In addition, food appears to have a more pronounced effect on the solubility of alpelisib than gastric pH.
When coadministered with a single 300 mg dose of alpelisib, ranitidine decreased the absorption and overall exposure of alpelisib.
Following administration of ranitidine with a low-fat low-calorie meal, the mean AUC and Cmax of alpelisib was decreased by 21% and 36%, respectively.
Administration of ranitidine under fasting conditions reduced the mean AUC and Cmax of alpelisib by 30% and 51%, respectively.
MANAGEMENT: To ensure maximal oral absorption, alpelisib should be administered with a meal.
Alpelisib Drug Interaction
Moderate: paclitaxel protein-bound, doxorubicin, empagliflozinUnknown: exemestane, trastuzumab, loperamide, cholecalciferol
Alpelisib Disease Interaction
Moderate: cutaneous manifestations, diabetes, diarrhea, osteonecrosis of the jaw, pneumonitis, renal impairment
Volume of Distribution
The apparent volume of distribution at steady state is 114L.
Elimination Route
Alpelisib reached a peak concentration in plasma of 1320±912ng/mL after 2 hours. Alpelisib has an AUClast of 11,100±3760h ng/mL and an AUCINF of 11,100±3770h ng/mL. A large, high fat meal increases the AUC by 73% and Cmax by 84% while a small, low fat meal increases the AUC by 77% and Cmax by 145%.
Half Life
The mean half life of alprelisib is 8 to 9 hours.
Clearance
The mean apparent oral clearance was 39.0L/h. The predicted clearance is 9.2L/hr under fed conditions.
Elimination Route
36% of an oral dose is eliminated as unchanged drug in the feces and 32% as the primary metabolite BZG791 in the feces. 2% of an oral dose is eliminated in the urine as unchanged drug and 7.1% as the primary metabolite BZG791. In total 81% of an oral dose is eliminated in the feces and 14% is eliminated in the urine.
Innovators Monograph
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