Physiologically Based Pharmacokinetic Modeling of Valemetostat to Inform Dose Recommendations When Coadministered...

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.