Population pharmacokinetics of total and unbound valemetostat and platelet dynamics in healthy volunteers and patients with non-Hodgkin lymphoma

Valemetostat, an EZH2/1 inhibitor, has been approved in Japan for treating relapsed/refractory adult T-cell leukemia/lymphoma, primarily based on results from a single-arm phase II trial. It is also being investigated globally for the treatment of other non-Hodgkin lymphomas (NHLs), including peripheral T-cell lymphoma, as well as for solid tumors. Researchers conducted a semi-mechanistic population pharmacokinetic study of both total and unbound valemetostat, along with an analysis of platelet count changes during treatment, using data from five clinical trials—two involving NHL patients and three with healthy volunteers. The pharmacokinetic analysis DS-3201 included 3,162 total and 1,871 unbound valemetostat observations from 102 patients and 72 healthy volunteers, described by a three-compartment model featuring sequential zero- and first-order absorption and saturable binding in the central compartment. Alpha-1-acid glycoprotein (AAG) emerged as the most significant covariate affecting total valemetostat exposure, though it had minimal impact on unbound exposure, indicating that dose adjustments based on AAG levels were unnecessary. The longitudinal platelet data from 101 patients (2,313 observations) were effectively modeled using a modified Friberg model with two proliferation compartments, which captured the spontaneous recovery of platelet counts without the need for dose modifications. A model-based simulation quantitatively evaluated proposed dose-adjustment guidelines in cases of decreased platelet counts by comparing the likelihood of treatment discontinuation due to platelet reduction, with or without dose adjustment. In conclusion, the models successfully described the observed total and unbound valemetostat concentrations, as well as the unique platelet time course during treatment, supporting the clinical dosing strategy and providing guidance for dose adjustments.