o induce an increase in estrogen receptor (ER)transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased antitumoractivity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CAmutated breast cancer cell lines.
12.2 Pharmacodynamics
Cardiac Electrophysiology
Serial ECGs were collected following a single dose and at steady-state to eva luate the effect of alpelisib on theQTcF interval in patients with advanced cancer. An analysis of clinical ECG data demonstrates the absence of alarge effect (i.e., > 20 ms) on QTcF prolongation at the recommended 300 mg dose with or without fulvestrant.
12.3 Pharmacokinetics
The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with solid tumors.
Steady-state alpelisib maximum plasma concentration (Cmax) and AUC increased proportionally over the doserange of 30 mg to 450 mg (0.1 to 1.5 times the approved recommended dosage) under fed conditions. The meanaccumulation of alpelisib is 1.3 to 1.5 and steady-state plasma concentrations are reached within 3 daysfollowing daily dosage. In adult patients who received PIQRAY 300 mg once daily in the SOLAR-1 trial,population approach derived mean steady-state alpelisib [coefficient of variation (CV%)] for Cmax was 2480(23%) ng/mL and AUC0-24hr was 33224 (21%) ng*h/mL.
Absorption
The median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 4.0 hours.
Effect of food
A high-fat high-calorie meal (985 calories with 58.1 g of fat) increased alpelisib AUC by 73% and Cmax by 84%,and a low-fat low-calorie meal (334 calories with 8.7 g of fat) increased alpelisib AUC by 77% and Cmax by145% following a single dose of PIQRAY. No clinically significant differences in alpelisib AUC were observed
between low-fat low-calorie and high-fat high-calorie meals.
Distribution
The mean (% CV) apparent volume of distribution of alpelisib at steady-state is predicted to be 114 L (46%).
Protein binding of alpelisib is 89% and is independent of concentration.
Elimination
The half-life of alpelisib is predicted to be 8 to 9 hours. The mean (% CV) clearance of alpelisib is predicted tobe 9.2 L/hr (21%) under fed conditions.
Metabolism
Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite BZG791 and toa lesser extent by CYP3A4, in vitro.
Excretion
Following a single oral dose of 400 mg radiolabeled alpelisib under fasted condition, 81% of the administereddose was recovered in feces (36% unchanged, 32% BZG791) and 14% (2% unchanged, 7.1% BZG791) inurine. CYP3A4-mediated metabolites (12%) and glucuronides amounted to approximately 15% of the dose.
Specific Populations
No clinically significant differences in the pharmacokinetics of alpelisib were predicted based on age (21 to 87years), sex, race/ethnicity (Japanese or Caucasian), body weight (37 to 181 kg), mild to moderate renalimpairment (CLcr 30 to < 90 mL/min based on the Cockcroft-Gault formula), or mild to severe hepaticimpairment (Child-Pugh Class A, B, and C). The effect of severe renal impairment (CLcr < 30 mL/min) on thepharmacokinetics of alpelisib is unknown.
Drug Interaction Studies
Clinical Studies
Acid Reducing Agents: PIQRAY can be coadministered with acid reducing agents, since PIQRAY should betaken with food. Food exhibited a more pronounced effect on the solubility of alpelisib th |
