Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

13.2 Pharmacodynamics
Elacestrant exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.
Cardiac Electrophysiology
ORSERDU does not cause a mean increase in QTc interval > 20 msec at the approved recommended dose.

Pharmacokinetic Properties

13.3 Pharmacokinetics
The steady-state mean (%CV) maximum concentration (Cmax) of elacestrant is 119 ng/mL (43.6%) and the area under the concentration-time curve (AUC0-24h) is 2440 ng*h/mL (44.3%) after administration of the recommended dosage of 345 mg once daily. The Cmax and AUC of elacestrant increase more than proportionally over a dosage range from 43 mg to 862 mg once daily (0.125 to 2.5 times the approved recommended dosage). Steady state is reached by Day 6 and the mean accumulation ratio based on AUC0-24h is 2-fold.
Absorption
The time to achieve peak plasma concentration (tmax) ranges from 1 to 4 hours. The elacestrant oral bioavailability is approximately 10%.
Effect of Food
Administration of ORSERDU 345 mg with a high-fat meal (800 to 1000 calories, 50% fat) increased Cmax by 42% and AUC by 22% compared to fasted administration.
Distribution
The estimated apparent volume of distribution is 5800L. Plasma protein binding of elacestrant is >99% and independent of concentration.
Elimination
The elimination half-life of elacestrant is 30 to 50 hours. The estimated mean (% CV) clearance of elacestrant is 186 L/hr (43.5%) and renal clearance is ≤ 0.14 L/hr.
Metabolism
Elacestrant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2A6 and CYP2C9.
Excretion
Following a single radiolabeled oral dose of 345 mg, 82% was recovered in feces (34% unchanged) and 7.5% was recovered in urine (< 1% unchanged).
Specific Populations
There were no clinically significant differences in the pharmacokinetics of elacestrant based on age (24 to 89 years), sex, and body weight (41 to 143 kg).
Patients with Hepatic Impairment
There were no clinically significant differences in the Cmax and AUC of elacestrant in subjects with mild hepatic impairment (Child-Pugh A). The AUC of elacestrant increased in subjects with moderate hepatic impairment (Child-Pugh B) by 83%.
Elacestrant has not been studied in subjects with severe hepatic impairment (Child-Pugh C).
Drug Interaction Studies
Clinical Studies
There were no clinically significant differences in the pharmacokinetics of elacestrant when used concomitantly with cimetidine (weak CYP3A inhibitor), omeprazole (gastric acid-reducing agent), or warfarin (highly protein-bound drug).
Table 5 describes the effect of other drugs on the pharmacokinetics of elacestrant and Table 6 describes the effect of elacestrant on the pharmacokinetics of other drugs.



Table 5: Effect of Other Drugs on Elacestrant
Fold Increased or Percent
Decrease of Elacestrant With
Concomitant Drug
Elacestrant
Concomitant Drug                                          Dose              Cmax             AUC CYP3A Inhibitors
Strong Inhibitor                                       172 mg once          4.4               5.3 daily
Itraconazole
Moderate Inhibitor                                    345 mg single         1.6               2.3 dose
Fluconazolea

CYP3A Inducers
Strong Inducer                                        345 mg single         73%              86% dose
Rifampin
Moderate Inducer                                      345 mg single       44-63%           55-73% dose
Efavirenza aPredicted   changes in Cmax and AUC of elacestrant.
Table 6: Effect of Elacestrant on Other Drugs
Fold Increase of Concomitant
Drug With Elacestrant
Elacestrant
Concomitant Drug                                          Dose              Cmax             AUC Substrate of P-gp
Digoxin                                               345 mg single         1.3               1.1 dose
Substrate of BCRP
Rosuvastatin                                          345 mg single         1.5               1.2 dose

In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Elacestrant is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
Elacestrant is not an inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A.
Transporter Systems: Elacestrant is a substrate for OATP2B1, but not P-gp.
Elacestrant is not an inhibitor of OAT1, OAT3, OCT2, MATE1, MATE2-K, OCT1, OATP1B1, OATP1B3 or OATP2B1.