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

ABSTRACT

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.