Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

9.2 Pharmacodynamics
An increase in selinexor exposure was associated with an increase in the probability of dose modification and some adverse reactions.
Cardiac Electrophysiology
The effect of multiple doses of Xpovio, up to 175 mg (2.2 times the maximum approved recommended dose) twice weekly, on the QTc interval was evaluated in patients with heavily pretreated hematologic malignancies. Xpovio had no large effect (i.e. no greater than 20 ms) on QTc interval at the therapeutic dose level.

Pharmacokinetic Properties

9.3 Pharmacokinetics
2             2
Selinexor Cmax and AUC increased proportionally over a dose range from 3 mg/m to 85 mg/m (0.06 to 1.8 times 2 the maximum approved recommended dose, based on 1.7 m body surface area). No clinically relevant accumulation at steady state was observed. Selinexor Cmax and AUC0-INF after administration of a single dose of Xpovio in patients with hematologic malignancies are presented in Table 8.
Table 10: Selinexor Cmax and AUC After Administration of a Single Dose of Xpovio 
Xpovio Dose
Mean (SD)                     60 mg                    80 mg                  100 mg Cmax (ng/mL)                 442 (188)                680 (124)              693 (201) AUC0-INF (ng·h/mL)         4,096 (1,185)            5,386 (1,116)           6,998 (818) 
Absorption

The Cmax is reached within 4 hours following oral administration of Xpovio.
Effect of Food
Concomitant administration of a high-fat meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) did not affect the pharmacokinetics of selinexor to a clinically significant extent.
Distribution
The apparent volume of distribution of selinexor is 133 L in patients with cancer. The protein binding of selinexor is 95%.
Elimination
Following a single dose of Xpovio, the mean half-life is 6 to 8 hours. The apparent total clearance of selinexor is 18.6 L/h in patients with cancer.


Metabolism
Selinexor is metabolized by CYP3A4, multiple UDP-glucuronosyltransferases (UGTs) and glutathione S- transferases (GSTs).
Specific Populations
No clinically significant differences in the pharmacokinetics of selinexor were observed based on age (18 to 94 years old), sex, body weight (36 to 168 kg), ethnicity, mild to severe renal impairment (CLCR: 15 to 89 mL/min, estimated by the Cockcroft-Gault equation), and disease type (hematological non-DLBCL, solid tumor, DLBCL). The effect of end-stage renal disease (CLCR <15 mL/min) or hemodialysis on selinexor pharmacokinetics is unknown.
Mild hepatic impairment had no clinically significant effect on the pharmacokinetics of selinexor. The effect of moderate and severe hepatic impairment on selinexor pharmacokinetics is unknown.
Drug Interaction Studies
Clinical Studies
Acetaminophen: No clinically significant differences in selinexor pharmacokinetics were observed when co- administered with acetaminophen (up to 1,000 mg daily dose of acetaminophen).
Clarithromycin (a strong CYP3A4 inhibitor): No clinically significant differences in selinexor pharmacokinetics were observed when co-administered with clarithromycin (up to 1,000 mg daily dose of clarithromycin).


In vitro Studies
CYP Enzymes: Selinexor does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Selinexor is not a CYP3A4, CYP1A2, or CYP2B6 inducer. Non-CYP Enzyme Systems: Selinexor is a substrate of UGTs and GSTs.
Transporter Systems: Selinexor inhibits OATP1B3 but does not inhibit other solute carrier (SLC) transporters.
Selinexor is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K.