Physiologically Based Pharmacokinetic Modeling of Valemetostat to Inform Dose Recommendations When Coadministered With CYP3A/P-gp Modulators

Valemetostat tosylate (valemetostat) is an oral, potent, selective dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, approved in Japan for the treatment of relapsed/refractory adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma. Results from in vitro and clinical studies suggest that valemetostat is pre-systemically metabolized by cytochrome P450 3A (CYP3A) in the gut and excreted into bile and urine via P-glycoprotein (P-gp) in its unchanged form and as an oxidative metabolite. In this study, a physiologically based pharmacokinetic (PBPK) model was developed by utilizing available in vitro and clinical pharmacokinetics (PK) data to predict the impact of CYP3A and P-gp modulators on the PK of valemetostat. The developed PBPK model was validated against clinical drug–drug interaction studies with a moderate CYP3A inhibitor (fluconazole), a strong CYP3A/P-gp dual inhibitor (itraconazole), and a strong CYP3A/P-gp dual inducer (rifampicin), indicating that the contributions of CYP3A and P-gp in the gut and liver to valemetostat PK were appropriately described in the PBPK model. The validated model was applied to assess the effect of either a CYP3A or a P-gp inhibitor, or a moderate CYP3A inducer on valemetostat PK. The PBPK model incorporating the contribution of CYP3A and P-gp in the gut and liver effectively estimated the effect of CYP3A/P-gp modulators on valemetostat PK and can be used to inform dose recommendations for valemetostat upon coadministration with other treatments.