Alpelisib

441.4704896

441.47

08W5N2C97Q

DTXSID70153355

C94214

L01XE|L - Antineoplastic and immunomodulating agents

29341000

129

3.2

1.391

1.587

P260, P314, P501

H373

|Warning|H373 (100%): Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]|P260, P314, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory.

**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.[MSDS] 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.

In the prelicensure clinical trials of alpelisib in patients with cancer, liver test abnormalities were frequent although usually transient, asymptomatic, and mild-to-moderate in severity. Some degree of ALT elevation arose in up to 44% of alpelisib- and fulvestrant-treated patients, but were above 5 times the upper limit of normal (ULN) in only 3% to 4%. The aminotransferase elevations rarely necessitated dose modifications or interruptions, and only slightly lower rates of enzyme elevations occurred in patients taking fulvestrant without alpelisib. In these trials that enrolled less than 1000 patients, there were several reports of marked serum aminotransferase elevations that led to early discontinuation. However, the nature and clinical features of the liver injury were not provided and there were no cases of clinically apparent liver injury. Skin rashes were also common with alpelisib therapy, and patients are often given prophylactic antihistamines which appear to result in fewer and milder rashes. However, moderate-to-severe rash can occur and some are accompanied by drug reaction with eosinophilia and systemic signs (DRESS) syndrome, some degree of liver injury (usually anicteric and asymptomatic) being a part of the manifestations.

Alpelisib is 89% protein bound.

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.|FDA Label|Treatment of breast cancer|Piqray is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine therapy as monotherapy (see section 5.1).|Treatment of PIK3CA related overgrowth spectrum|Drug: Alpelisib

Alpelisib is an oral selective inhibitor of the phosphoinositol-3-kinase (PIK3) which is mutated in several forms of solid tumors and is approved for use in specific forms of advanced or metastatic breast cancer. Serum aminotransferase elevations are common during alpelisib therapy but clinically apparent liver injury with jaundice has not been reported with its use and must be rare, if it occurs at all.

Antineoplastic Agents, Kinase Inhibitors

Alpelisib does not prolong the QTcF interval. Patients taking alpelisib experience a dose dependent benefit from treatment with a 51% advantage of a 200mg daily dose over a 100mg dose and a 22% advantage of 300mg once daily over 150mg twice daily. This suggests patients requiring a lower dose may benefit from twice daily dosing.

Alpelisib reached a peak concentration in plasma of 1320±912ng/mL after 2 hours. Alpelisib has an AUC_last of 11,100±3760h ng/mL and an AUC_INF of 11,100±3770h ng/mL. A large, high fat meal increases the AUC by 73% and C_max by 84% while a small, low fat meal increases the AUC by 77% and C_max by 145%.|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.|The apparent volume of distribution at steady state is 114L.|The mean apparent oral clearance was 39.0L/h. The predicted clearance is 9.2L/hr under fed conditions.

Alpelisib is metabolized by hydrolysis reactions to form the primary metabolite. It is also metabolized by CYP3A4. The full metabolism of Alpelisib has yet to be determined but a series of reactions have been proposed. The main metabolic reaction is the substitution of an amine group on alpelisib for a hydroxyl group to form a metabolite known as M4 or BZG791. Alpelisib can also be glucuronidated to form the M1 and M12 metabolites.

The mean half life of alprelisib is 8 to 9 hours.

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.

Alpelisib

Human Drugs -> EU pediatric investigation plans|Human drugs -> Piqray -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients