In this article, we will discuss Selinexor (Mechanism of Action). So, let’s get started.
Mechanism of Action
In nonclinical studies, selinexor reversibly inhibits nuclear export of tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). XPO1 inhibition by selinexor leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins, such as c‐myc and cyclin D1, cell cycle arrest, and apoptosis of cancer cells. Selinexor demonstrated pro‐apoptotic activity in vitro in multiple myeloma cell lines and patient tumor samples, and in murine xenograft models.
Selinexor exposure‐response relationships and the time course of pharmacodynamic responses are unknown.
The effect of multiple doses of Selinexor, up to 175 mg (2.2 times the approved recommended dose) twice weekly, on the QTc interval was evaluated in patients with heavily pretreated hematologic malignancies.
Selinexor had no large effect (i.e. no greater than 20 ms) on QTc interval at the therapeutic dose level.
Following a single‐dose administration of selinexor 80 mg, the mean (standard deviation) peak plasma concentration (Cmax) was 680 (124) ng/mL and the mean AUC was 5386 (1116) ng•h/mL. Selinexor Cmax and AUC increased proportionally over doses from 3 mg/m2 to 85 mg/m2 (0.06 to 1.8 times the approved recommended dose based on 1.7 m2 body surface area). No clinically relevant accumulation at steady state was observed.
The Cmax is reached within 4 hours following oral administration of selinexor.
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.
The apparent volume of distribution of selinexor is 125 L in patients with cancer. The protein binding of selinexor is 95%.
Following a single dose of XPOVIO, the mean half‐life is 6 to 8 hours. The apparent total clearance of selinexor is 17.9 L/h in patients with cancer.
Selinexor is metabolized by CYP3A4, multiple UDP‐glucuronosyltransferases (UGTs) and glutathione S‐transferases (GSTs)