h‐fat meal (800 to 1,000 calories with approximately 50% of total caloriccontent 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 125 L in patients with cancer. The protein binding ofselinexor is 95%.
Elimination
Following a single dose of XPOVIO, the mean half‐life is 6 to 8 hours. The apparent total clearance of selinexoris 17.9 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 94years old), sex, ethnicity, mild to severe renal impairment (CLCR: 15 to 89 mL/min, estimated by the Cockcroft‐Gault equation). 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 thepharmacokinetics of selinexor. The effect of moderate and severe hepatic impairment on selinexorpharmacokinetics is unknown.
Drug Interaction Studies
Clinical Studies
No dedicated drug interaction studies have been performed with XPOVIO.
In vitro Studies
CYP Enzymes: Selinexor does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Selinexor isnot a CYP3A4, CYP1A2, or CYP2B6 inducer. Selinexor is a substrate of CYP3A4.
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with selinexor.
Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic ineither the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.
Fertility studies in animals have not been conducted with selinexor. In repeat‐dose oral toxicity studies,selinexor was administered for up to 13 weeks in rats and monkeys. Reduced sperm, spermatids, and germcells in epididymides and testes were observed in rats at ≥1 mg/kg, decreased ovarian follicles were observed
in rats at ≥2 mg/kg, and single cell necrosis of testes was observed in monkeys at ≥1.5 mg/kg. These doselevels resulted in systemic exposures approximately 0.11, 0.28, and 0.53 times, respectively, the exposure(AUClast) in humans at the recommended human dose of 80 mg.
14 CLINICAL STUDIES
14.1 Relapsed Refractory Multiple Myeloma
The efficacy of XPOVIO plus dexamethasone was eva luated in STORM (KCP‐330‐012; NCT02336815).
STORMwas a multicenter, single‐arm, open‐label study of patients with RRMM. STORM Part 2 included 122 patientswith RRMM who had previously received three or more anti‐myeloma treatment regimens including analkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti‐CD38monoclonal antibody; and whose myeloma was documented to be refractory to glucocorticoids, a proteasomeinhibitor, an immunomodulatory agent, an anti‐CD38 monoclonal antibody, and to the last line of therapy. |
