Abstract Valemetostat is a dual inhibitor of EZH2/1 approved in Japan for the treatment of relapsed/refractory (R/R) adult T–cell lymphoma/leukemia (ATLL) and R/R peripheral T–cell lymphoma (PTCL). It is administered orally once daily (QD) at 200 mg. Here, we present comprehensive population pharmacokinetic (PPK) and exposure–response (ER) analyses of valemetostat. The PPK model included data from six clinical trials in patients with non–Hodgkin lymphoma, including ATLL/PTCL, or healthy participants. ER efficacy analyses were based on data from one phase 2 clinical trial in patients with PTCL; ER safety analyses used data from three trials in patients with ATLL or PTCL. Valemetostat unbound average concentration up to event was used as the exposure metric. ER analyses included overall response rates for efficacy and six safety endpoints (any Grade ≥3 treatment–emergent adverse event TEAE; Grade ≥3 thrombocytopenia, anemia, and neutropenia; and dose reduction and interruption due to TEAEs). Valemetostat pharmacokinetics were well described by a three–compartment model, with a sequential linked zero–/first–order absorption, a saturable binding component in the central compartment, and linear elimination of unbound valemetostat from the central compartment. Alpha‐1‐acid glycoprotein was the only identified covariate significantly affecting total valemetostat exposure but had no impact on unbound exposure. The ER relationship on efficacy was not significant, and positive relationships were identified for multiple safety endpoints. Safety simulations across different doses suggested an acceptable safety profile for 200 mg QD. Overall, these analyses support the favorable benefit–risk profile of valemetostat at 200 mg QD in patients with R/R PTCL.
Inoue et al. (Sat,) studied this question.