Selinexor population pharmacokinetic and exposure–response analyses to support dose optimization in patients with diffuse large B-cell lymphoma

Characterize the population PK and exposure–response (ER) relationships of selinexor in patients with diffuse large B-cell lymphoma (DLBCL) (efficacy endpoints) or other non-Hodgkin’s lymphoma (NHL) patients (safety endpoints) to determine the optimal dose in patients with DLBCL. This work included patients from seven clinical studies, with 800 patients for PK, 175 patients for efficacy and 322 patients for safety analyses. Logistic regression models and Cox-regression models were used for binary and time-to-event endpoints, respectively. Model-based simulations were performed to justify dose based on balance between efficacy and safety outcome. Selinexor pharmacokinetics were well-described by a two-compartment model with body weight as a significant covariate on clearance and central volume of distribution and gender on clearance. Overall response rate (ORR) in patients with DLBCL increased with day 1 Cmax and decreased in patients with higher baseline tumor size (p < 0.05). Significant exposure–safety relationships (p < 0.05) in NHL patients were identified for the frequency of the following safety endpoints: dose modifications, decreased appetite Grade ≥ 3 (Gr3+), fatigue Gr2+, vision blurred Gr1+, and vomiting Gr2+. Similar exposure–safety relationships were found for time-to-onset of the adverse events. Simulations of the safety and efficacy ER models suggested that, compared to a starting dose of 60 mg twice weekly (BIW), a 40 mg BIW regimen resulted in an absolute decrease in AE probabilities between 1.9 and 5.3%, with a clinically significant absolute efficacy decrease of 4.7% in ORR. The modeling results support that 60 mg BIW is the optimal dose in patients with DLBCL.