Pharmacokinetics of Selinexor: The First-in-Class Selective Inhibitor of Nuclear Export

The functionality of many tumor suppressor proteins (TSPs) and oncoprotein transcript RNAs largely depend on their location within the cell. The exportin 1 complex (XPO1) transports many of these molecules from the nucleus into the cytoplasm, thereby inactivating TSPs and activating oncoprotein transcript RNAs. Aberrations of these molecules or XPO1 can increase this translocation process, leading to oncogenesis. Selinexor is a selective inhibitor of nuclear export and is an active agent in various malignancies. It is currently approved for relapsed or refractory diffuse large B-cell lymphoma as well as multiple myeloma. Following oral administration, selinexor exhibits linear and time-independent pharmacokinetics (PK) across a wide dose range, with moderately rapid absorption (time to reach maximum concentration [T_max] 2-4 h) and moderate elimination (half-life [t_½] 6-8 h). Selinexor PK observed among patients with various solid tumors and hematologic malignancies is consistent irrespective of disease. Population PK analyses demonstrated the PK of selinexor is well-described by a two-compartment model, with significant relationships for body weight on apparent clearance and apparent central volume of distribution, and sex on apparent clearance, which result in clinically non-relevant changes in exposure. These analyses also suggested selinexor PK are not significantly impacted by various concomitant medications and organ dysfunction (hepatic/renal). The time course of selinexor PK appears similar between pediatric and adult patients, although higher exposures have been observed among pediatric patients relative to adults administered similar milligrams per meter squared (mg/m²) doses of selinexor.